JP2009530347A - Benzimidazoles having activity at the M1 receptor and their use in medicine - Google Patents

Abstract

Provided are compounds, salts and solvates of formula (I), wherein Q, R and R6 are as defined in the claims. Also disclosed is the use of the compounds for therapy aimed at treating, for example, psychotic and cognitive disorders.

Description

  The present invention relates to novel compounds, pharmaceutical compositions containing them and their use in therapy, in particular as antipsychotics.

Muscarinic acetylcholine receptors are members of the G protein-coupled receptor superfamily that mediate the action of the neurotransmitter acetylcholine in both the central and peripheral nervous systems. Five muscarinic receptor subtypes M ₁ ~M ₅ have been cloned. Muscarinic M ₁ receptors are mainly expressed in the cerebral cortex and hippocampus, but are also expressed in the periphery such as exocrine glands.

Muscarinic receptors in the central nervous system, in particular play an important role in M ₁ is mediating higher recognition process. Diseases associated with cognitive impairment, such as Alzheimer's disease, involve a lack of cholinergic neurons in the basal forebrain. Furthermore, in animal models, blockage or injury of the central cholinergic pathway results in significant cognitive deficits.

  Cholinergic replacement therapy is primarily based on the use of acetylcholinesterase inhibitors to prevent the degradation of endogenous acetylcholine. These compounds are clinically effective against symptomatic cognitive decline, but cause side effects caused by stimulation of peripheral muscarinic receptors, including gastrointestinal motility disorders and nausea.

  The dopamine hypothesis of schizophrenia suggests the usefulness of dopamine receptor antagonists for the reduction of psychiatric symptoms, as excessive dopaminergic stimulation is responsible for the positive symptoms of the disease. However, conventional dopamine receptor antagonists can cause extrapyramidal side effects (EPS), including tremor and tardive dyskinesia, in patients.

M ₁ receptor agonists are sought for symptomatic treatment of cognitive decline. More recently, several groups have shown that muscarinic receptor agonists exhibit atypical antipsychotic-like properties within the preclinical paradigm. The muscarinic agent xanomeline is an amphetamine-induced gait in rats, apomorphine-induced climbing in mice, dopamine agonist-induced swirling in unilateral 6-OH-DA-injured rats, and monkeys. Reversing several dopamine-induced behaviors, including amphetamine-induced motor anxiety (no EPS tendency). It has also been shown to inhibit A10 (not A9) dopamine cell firing and condition avoidance in rats and induce c-fos expression in the prefrontal cortex and nucleus accumbens but not in the striatum. Yes. All of these data suggest atypical antipsychotic-like properties.

  Xanomeline has also been shown to reduce psychiatric symptoms such as suspicious behavior, hallucinations and delusions in Alzheimer's patients. However, because this compound is relatively non-selective, dose-limiting peripheral cholinergic side effects occur.

In PCT / GB2006 / 003585, certain M ₁ receptor agonists are known. The present inventors have now discovered a novel group of compounds that are M ₁ receptor agonists.

［式中、
Ｒ^６は、水素、シアノ、ハロゲン、Ｃ_１−６アルキル、１以上のフッ素原子で置換されたＣ_１−６アルキル、Ｃ_１−６アルキルスルホニル、Ｃ_３−６シクロアルキル、１以上のフッ素原子で置換されたＣ_３−６シクロアルキル、Ｃ_１−６アルコキシ、および１以上のフッ素原子で置換されたＣ_１−６アルコキシから選択され；
Ｒは、Ｃ_１−６アルキル、Ｃ_３−６シクロアルキル、Ｃ_３−６シクロアルキルＣ_１−６アルキルおよびＣ_２−６アルキニル（いずれのアルキル基またはシクロアルキル基も場合により１以上のフッ素原子で置換されてよい）から選択され；かつ
Ｑは水素またはＣ_１−６アルキルである］
の化合物またはその塩もしくは溶媒和物を提供する。 Thus, in a first aspect, the present invention provides a compound of formula (I):

[Where:
R ⁶ is hydrogen, cyano, _{halogen, C 1-6} alkyl, 1 or more _{C 1-6} alkyl substituted with a fluorine _{atom, C 1-6 alkylsulfonyl, C 3-6} cycloalkyl, one or more fluorine atoms in substituted _{C 3-6 cycloalkyl,} it is selected from _{C 1-6} alkoxy, and one or more _{C 1-6} alkoxy substituted with a fluorine atom;
R is C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-6 alkyl and C _2-6 alkynyl (any alkyl group or cycloalkyl group optionally has one or more fluorine atoms) And Q is hydrogen or C _1-6 alkyl]
Or a salt or solvate thereof.

（Ｉａ）
［式中、
Ｒ^６は、水素、ハロゲン、Ｃ_１−６アルキル、１以上のフッ素原子で置換されたＣ_１−６アルキル、Ｃ_３−６シクロアルキル、１以上のフッ素原子で置換されたＣ_３−６シクロアルキル、Ｃ_１−６アルコキシおよび１以上のフッ素原子で置換されたＣ_１−６アルコキシから選択され；
Ｒは、Ｃ_１−６アルキル、Ｃ_３−６シクロアルキル、Ｃ_３−６シクロアルキルＣ_１−６アルキル（いずれのアルキル基またはシクロアルキル基も場合により１以上のフッ素原子で置換されてよい）から選択され；かつ
Ｑは水素またはＣ_１−６アルキルである］
の化合物またはその薬学上許容される塩もしくは溶媒和物を提供する。 The present invention also provides a compound of formula (Ia):

(Ia)
[Where:
R ⁶ is hydrogen, _{halogen, C 1-6} alkyl, 1 or more _{C 1-6} alkyl substituted with a fluorine _{atom, C 3-6} cycloalkyl, the one or more _{C 3-6} cycloalkyl substituted with a fluorine atom alkyl _is selected from _{C 1-6} alkoxy and one or more _{C 1-6} alkoxy substituted with a fluorine atom;
R is C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-6 alkyl (any alkyl group or cycloalkyl group may optionally be substituted with one or more fluorine atoms) And Q is hydrogen or C _1-6 alkyl]
Or a pharmaceutically acceptable salt or solvate thereof.

As used herein, “alkyl” refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, C _1-6 alkyl means a straight or branched alkyl containing at least 1, and at most 6, carbon atoms. Examples include but are not limited to methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1,1-dimethylpropyl.

As used herein, “alkoxy” refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, C _1-6 alkoxy means a straight or branched alkoxy group containing at least one, at most 6 carbon atoms. Examples of “alkoxy” herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 1-methylethyl-oxy, 2-methylprop Examples include -1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy.

As used herein, “cycloalkyl” refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms. For example, C _3-6 cycloalkyl means a non-aromatic carbocyclic ring containing at least 3, and at most 6, ring carbons. Examples of “cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, “alkynyl” refers to a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds and a specified number of carbon atoms. For example, C _2-6 alkynyl means a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds and at least 2, and at most 6, carbon atoms. Examples of “alkynyl” as used herein include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

  As used herein, “halogen” (or abbreviation “halo”) is abbreviated as elemental fluorine (sometimes abbreviated as “fluoro” or “F”), chlorine (“chloro” or “Cl”). In some cases), bromine (sometimes abbreviated as “bromo” or “Br”) and iodine (sometimes abbreviated as “iodo” or “I”). Examples of halogen are fluorine, chlorine and bromine.

  As used herein, “solvate” refers to complexes of various stoichiometry formed by a solute (in the present invention, a compound of formula (I) or a salt thereof) and a solvent. Such solvents for the present invention can be those that do not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. The solvent used may be water, and this solvate is sometimes called a hydrate.

In the present specification, “substitution” refers to substitution with a designated substituent, and multiple substitution is possible unless otherwise specified. For example, there may be 1, 2, 3, or 4 substituents on a given substituent. For example, when R ⁶ is a C _1-6 alkyl group, it can be substituted with 1, 2, 3 or 4 fluoro groups; when R ⁶ is a C _1-6 alkoxy group, it is One, two, three or four fluoro groups can be substituted. For example, R ⁶ may be a C _1-6 alkyl group substituted with 3 fluoro groups; R ⁶ may be a C _1-6 alkoxy group substituted with 3 fluoro groups. For example, R ⁶ can be CF ₃ . Similarly, when R is a C _1-6 alkyl group substituted with one or more fluoro groups, it may be substituted with 1, 2, 3 or 4 fluoro groups; _When it is a _3-6 cycloalkyl group, it can be substituted with 1, 2, 3 or 4 fluoro groups. For example, R may be a C _1-6 alkyl group substituted with 3 fluoro groups; R may be a C _3-6 cycloalkyl group substituted with 3 fluoro groups. For example, R may be CF ₃ or CH ₂ F.

In one embodiment of the present invention, ^{R 6} is hydrogen, _{halogen, C 1-6} alkyl, _{C 1-6} alkyl substituted with one or more fluorine _{atoms, C 3-6 cycloalkyl, C 1-6} alkylsulfonyl, C _1-6 selected alkoxy, and one or more _{C 1-6} alkoxy substituted with a fluorine atom.

In one embodiment, R ⁶ is cyano.

In one embodiment of the present invention, ^{R 6} is hydrogen, cyano, _{halogen, C 1-6} alkyl, 1, 2 or 3 _{C 1-6} alkyl substituted with a fluorine _{atom, C 3-6} cycloalkyl , _{C 1-6 alkylsulfonyl, C 1-6} alkoxy, and one is selected from 2 or 3 _{C 1-6} alkoxy substituted with a fluorine atom.

In one embodiment, ^{R 6} is hydrogen, _{halogen, C 1-3} alkyl, 1 or more _{C 1-3} alkyl substituted with a fluorine _{atom, C 3-4 cycloalkyl, C 1-3 alkylsulfonyl, C 1- 3} is selected alkoxy, and one or more C _1-3 alkoxy substituted by a fluorine atom.

In one embodiment, ^{R 6} is hydrogen, _{halogen, C 1-3} alkyl, one or two _{C 1-3} alkyl substituted with a fluorine _{atom, C 3-4 cycloalkyl, C 1-3} alkylsulfonyl, C _1-3 alkoxy, and one is selected from 2 or 3 _{C 1-3} alkoxy substituted by a fluorine atom.

In one embodiment of the present invention, ^{R 6} is substituted _{halogen, C 1-6} alkyl, 1 or more _{C 1-6} alkyl substituted with a fluorine _{atom, C 3-6} cycloalkyl, in one or more fluorine atoms C _{3-6 cycloalkyl,} is selected from _{C 1-6} alkoxy and one or more _{C 1-6} alkoxy substituted with a fluorine atom.

In one embodiment of the invention, R ⁶ is selected from hydrogen, cyano, fluoro, bromo, methyl, ethyl, methoxy, trifluoromethoxy, methylsulfonyl, trifluoromethyl and cyclopropyl.

In one embodiment of the invention, R ⁶ is selected from fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, trifluoromethoxy and trifluoromethyl. In a further embodiment of the invention R ⁶ is selected from chloro, bromo, methyl, ethyl, isopropyl, methoxy, trifluoromethoxy and trifluoromethyl. For example, R ⁶ is methyl.

In one embodiment, R is selected from C _1-6 alkyl, C _3-6 cycloalkyl and C _3-6 cycloalkyl C _1-6 alkyl, any alkyl or cycloalkyl group optionally It may be substituted with one or three fluorine atoms.

In one embodiment, R is selected from C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl and C _2-4 alkynyl, wherein any alkyl or cycloalkyl group is Optionally, it may be substituted with 1, 2 or 3 fluorine atoms.

In one embodiment, R is C _2-6 alkynyl. In one embodiment, R is C _2-4 alkynyl. In one embodiment, R is propynyl.

In a further embodiment of the invention, R is selected from C _1-3 alkyl and C _3-6 cycloalkyl C _1-3 alkyl, and any alkyl or cycloalkyl group (eg, alkyl group) is optionally one or more. May be substituted with a fluorine atom.

  In a further embodiment, R is selected from methyl, ethyl, propyl, isopropyl and cyclopropylmethyl. In one embodiment, R is selected from methyl, ethyl, propyl and isopropyl.

In one embodiment of the invention, R is selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkylC _1-6 alkyl, any alkyl group optionally having one or more fluorine atoms. May be substituted.

In one embodiment of the invention, R is selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-6 alkyl and C _2-4 alkynyl, and any alkyl group or cyclo The alkyl group may also be optionally substituted with 1, 2 or 3 fluorine atoms.

In a further embodiment, R is selected from methyl, ethyl, propyl, isopropyl, CF ₃ , cyclopropylmethyl, propynyl and cyclobutyl.

In one embodiment of the invention, Q is selected from hydrogen and C _1-3 alkyl. In a further embodiment, Q is selected from hydrogen, methyl, ethyl and propyl. In one embodiment, Q represents hydrogen or methyl. In one embodiment, Q is hydrogen.

  In one embodiment, the salt or solvate of the compound of formula (I) is a pharmaceutically acceptable salt or solvate. In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

  For use in medicine, it is believed that the salt of formula (I) should be pharmaceutically acceptable. Suitable salts will be apparent to those skilled in the art and include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid phosphoric acid, hydroiodic acid, phosphoric acid or metaphosphoric acid; and tartaric acid, acetic acid, Trifluoroacetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, formic acid, propionic acid, glycolic acid, gluconic acid, maleic acid, succinic acid, (1S)-(−)-10-camphorsulfonic acid, ( 1S)-(+)-10-camphorsulfonic acid, isothioic acid, mucoic acid, gentisic acid, isonicotinic acid, saccharic acid, glucuronic acid, furoic acid, glutamic acid, ascorbic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid , Embonic acid (pamo acid), methane sulfonic acid, ethane sulfonic acid, pantothenic acid, stearic acid, sulfinyl acid, al Monobasic formed with organic acids such as acid, galacturonic acid and aryl sulfonic acids, for example naphthalene-1,5-disulfonic acid, naphthalene-1,3-disulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid Or a dibasic salt is mentioned. Other pharmaceutically unacceptable salts such as oxalate may also be used, for example, for the isolation of compounds of formula (I) and are included within the scope of the present invention. The compounds of the present invention may be in the form of their free bases or pharmaceutically acceptable salts thereof, particularly monohydrochloride, monoformate or monotrifluoroacetate.

  Some of the compounds of formula (I) may form acid addition salts with less than 1 equivalent (eg, 0.5 equivalents of dibasic acid) or 1 equivalent or more of acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

It is believed that compounds of formula (I) may exist in cis or trans isomeric forms (OR groups on the cyclohexane ring with respect to piperidine substituents).
Cis type:

The trans form can be drawn in the following different ways, but both are considered to represent the same isomeric form.

  The individual isomers (cis and trans) and mixtures thereof are included within the scope of the present invention. These isomers can be separated from one another by conventional methods or by methods detailed in connection with the following compound examples. Any given isomer can be obtained by stereospecific or asymmetric synthesis. The invention also extends to tautomeric forms and mixtures thereof.

  In one embodiment, the compounds of formula (I) are trans isomers.

  In another embodiment, the compound of formula (I) is a cis isomer.

A mixture of cis and trans compounds, or compounds for which cis / trans conformation has not been determined are depicted herein as follows.

Compounds of the present invention include, but are not limited to, those specified in the Examples section and included below:
Cis-6-methyl-1- [1- (cis-4-methoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one trans-6-methyl-1- [1- (Cis-4-methoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6 -Methyl-1,3-dihydro-2H-benzimidazol-2-one 1- {1- [cis-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6-methyl-1,3-dihydro-2H- Benzimidazol-2-one 6-methyl-1- {1- [cis-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-di Dro-2H-benzimidazol-2-one 6-methyl-1- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6-Methyl-1- (1- {trans-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one 6-methyl-1 -{1- [cis-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6-methyl-1- {1- [trans -1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6-methyl -1- (1- {cis-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one or a salt or solvate thereof, For example, hydrochloride salt, trifluoroacetate salt or formate salt.

  In one embodiment, the salts of the compounds listed above are pharmaceutically acceptable salts.

Examples of the present invention include the following:
1.6-methyl-1- [1- (cis-4-methoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 2.6-methyl-1- [1- (Trans-4-methoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 3.1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6-methyl-1,3-dihydro-2H-benzimidazol-2-one 4.1- {1- [cis-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6-methyl-1,3- Dihydro-2H-benzimidazol-2-one 5.6-methyl-1- {1- [cis-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1, -Dihydro-2H-benzimidazol-2-one 6.6-methyl-1- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazole- 2-one 7.6-methyl-1- (1- {trans-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one 8.6-Methyl-1- {1- [cis-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 9.6 Methyl-1- {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazole 2-one 10.6-methyl-1- (1- {cis-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one 11. Cis- (1- [4- (Ethoxyl) cyclohexyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one Trans 1- (1- [4- (Ethoxyl) cyclohexyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one 13.1- {1- [trans-4- (ethyloxy) Cyclohexyl] -4-piperidinyl} -6-fluoro-1,3-dihydro-2H-benzimidazol-2-one 14.6-bromo-1- {1- [trans-4- (ethyloxy) cyclohexyl] -4- Piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 15.1- {1- [cis-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6- (trifluoromethyl) -1, 3-Dihydro-2H-benzimidazol-2-one 16.6-ethyl-1- {1- [trans-4- (ethyloxy) cyclohexyl -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 17.6-cyclopropyl-1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1, 3-Dihydro-2H-benzimidazol-2-one 18.1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6- (methyloxy) -1,3-dihydro-2H- Benzimidazol-2-one19. Cis-1- {1- [4- (ethoxy) cyclohexyl] -4-piperidinyl} -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one20. Trans-1- {1- [4- (ethoxy) cyclohexyl] -4-piperidinyl} -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one 21.6- Methyl-1- [1- (4-trifluoromethoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 22.1- (1- {cis-4-[(cyclo Propylmethyl) oxy] cyclohexyl} -4-piperidinyl) -6-methyl-1,3-dihydro-2H-benzimidazol-2-one 23.1- (1- {trans-4-[(cyclopropylmethyl) oxy Cyclohexyl} -4-piperidinyl) -6-methyl-1,3-dihydro-2H-benzimidazol-2-one Trans-6-methyl-1- [1- (4-cyclopropyloxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one Cis-1- (1- [4- (propyloxy) cyclohexyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one Trans-1- (1- [4- (propyloxy) cyclohexyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one 27.6-bromo-1- {1- [trans- 4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 28.6-ethyl-1- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 29.6-cyclopropyl-1- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1 , 3-Dihydro-2H-benzimidazol-2-one Cis-1- {1- [4- (propyloxy) cyclohexyl] -4-piperidinyl} -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one Trans-1- {1- [4- (propyloxy) cyclohexyl] -4-piperidinyl} -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one 32.1 -{1- [cis-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -6-methyl-1,3-dihydro-2H-benzimidazol-2-one 33.1- {1- [ Trans-4- (Ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -6-methyl-1,3-dihydro-2H-benzimidazol-2-one 34.6-methyl-1- {1- [cis -1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 35.6-methyl -1- {1- [frans-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro -2H- benzimidazol-2-one 36. Trans-6-methyl-1- [1- (1-ethyl-4-propoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 37.3- {1- [trans -4- (Ethyloxy) cyclohexyl] -4-piperidinyl} -2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile 38.3- {1- [trans-4- (ethyloxy) -1 -Methylcyclohexyl] -4-piperidinyl} -2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile 39.1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl } -6- (Methylsulfonyl) -1,3-dihydro-2H-benzimidazol-2-one 40.6-methyl-1 {1- [cis-4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 41.6-methyl-1- {1- [Trans-4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 42.1- {1- [trans-4- (ethyloxy ) -1-Methylcyclohexyl] -4-piperidinyl} -6-fluoro-1,3-dihydro-2H-benzimidazol-2-one 43.6-fluoro-1- {1- [trans-1-methyl-4] -(Methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 44.6-chloro-1- {1- [ Lance-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 45.6- (ethyloxy) -1- {1- [trans- 1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 46.6- (ethyloxy) -1- {1- [trans-4- (Ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 47.6-chloro-1- {1- [trans-4- (ethyloxy) -1 -Methylcyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one and its salts and solvates, For example hydrochloride, trifluoroacetate or formate.

  One skilled in the art will not recognize that certain protected derivatives of compounds of formula (I) (which can be prepared prior to the final deprotection step) have pharmacological activity per se, but in some cases After oral or parenteral administration, it can be metabolized in the body to form pharmacologically active compounds of the invention. Thus, such derivatives are sometimes referred to as “prodrugs”. In addition, certain compounds of the invention can serve as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of compounds of the invention are included within the scope of the invention. Examples of suitable protecting groups for the compounds of the invention are Drugs of Today, Volume 19, Number 9, 1983, pp 499-538 and Topics in Chemistry, Chapter 31, pp 306-316 and “Design of Prodrugs”, H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures of these documents are hereby incorporated by reference). Furthermore, the person skilled in the art can, for example, As known by Bundgaard in “Design of Prodrugs” (the disclosure content of this document is hereby incorporated by reference), a specific known to those skilled in the art as a “pro part” It will be appreciated that this moiety can be placed on a suitable functional group (if such a functional group is present in the compounds of the present invention). Suitable prodrugs for the compounds of the present invention include esters, carbonates, hemiesters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals and ketals. Can be mentioned.

化合物との式（ＩＩＩ）：

（式中、Ｒ^６’は上記で定義された基Ｒ^６、またはＲ^６へ変換可能な基であり、Ｒ’は上記で定義された基Ｒ、またはＲへ変換可能な基である）
の化合物をカップリングさせることを含む。 In a further aspect, the present invention provides a general method (A1) for preparing a compound of formula (I) wherein Q = H, the method comprising:
Formula (II):

Formula (III) with a compound:

Wherein R ^{6 ′} is a group R ⁶ or a group convertible to R ⁶ as defined above, and R ′ is a group R or a group convertible to R as defined above.
Coupling the compound.

  This reaction is carried out under conditions suitable for reductive alkylation. The reductive alkylation reaction is generally carried out with sodium triacetoxyborohydride in dichloroethane, optionally in the presence of triethylamine and optionally in the presence of titanium tetraisopropoxide. Alternatively, sodium cyanoborohydride can be used as a reducing reagent in a solvent such as methanol or ethanol, or reductive alkylation can be performed under catalytic hydrogenation conditions using a palladium catalyst. In a further variation, compounds (II) and (III) are condensed under dehydrating conditions such as molecular sieves or magnesium sulfate and the resulting imine or enamine is used, for example with sodium borohydride or catalytically It can be reduced by hydrogenation.

  This reaction produces a mixture of cis and trans isomers, which can be separated by chromatography or crystallization.

（式中、Ｒ^６’は上記で定義された基Ｒ^６、またはＲ^６へ変換可能な基であり、Ｒ’は上記で定義された基Ｒ、またはＲへ変換可能な基であり、ＱはＣ_１−６アルキルであり、Ｘはブロモまたはヨードまたはクロロである） When Q is C _1-6 alkyl, modification of the general method (A1) is necessary. Thus, in general method (A2), a compound of formula (II) is reacted with a compound of formula (III) in the presence of a cyanide source such as acetone cyanohydrin to form a cyano intermediate (XXXX). This can be reacted with an alkyl Grignard reagent QMgX to form a compound of formula (I) where Q is C _1-6 alkyl.

(Wherein R ^{6 ′} is a group R ⁶ defined above or a group convertible to R ⁶ , R ′ is a group R defined above or a group convertible to R, and Q Is C _1-6 alkyl and X is bromo or iodo or chloro)

  This reaction produces a mixture of cis and trans isomers, which can be separated by chromatography or crystallization.

の化合物と式（Ｖ）：

（式中、Ｒ^６’は上記で定義された基Ｒ^６、またはＲ^６へ変換可能な基であり、Ｒ’は上記で定義された基Ｒ、またはＲへ変換可能な基であり、Ｑは上記で定義された通りであり、ＸおよびＹは双方とも脱離基を表す）
の化合物をカップリングさせることを含む。ＸおよびＹは同じであっても異なっていてもよく、例としてはＣｌ、ＰｈＯ、ＥｔＯ、イミダゾールがある。ＸおよびＹが双方ともＣｌである、すなわちホスゲンである場合、この試薬は、例えばジホスゲンまたはトリホスゲンからin situで生成し得る。 In a further aspect, the present invention provides a general method (B) for preparing a compound of formula (I), the method comprising:
Formula (IV):

And a compound of formula (V):

Wherein R ^{6 ′} is a group R ⁶ defined above or a group convertible to R ⁶ , R ′ is a group R defined above or a group convertible to R, and Q Is as defined above, and X and Y both represent a leaving group)
Coupling the compound. X and Y may be the same or different and examples include Cl, PhO, EtO, imidazole. If X and Y are both Cl, ie phosgene, the reagent can be generated in situ from, for example, diphosgene or triphosgene.

  The above reaction may be performed by reacting diamine (IV) with reagent (V) in an inert solvent such as dichloromethane or toluene, optionally in the presence of a base such as triethylamine or potassium carbonate, optionally with heating. Using a traditional methodology.

  It is believed that the compound of formula (IV) may be a pure cis or trans isomer, or a mixture of isomers. If necessary, separation of the pure cis and trans isomers after reaction with (V) can be carried out by chromatography or crystallization.

（式中、Ｒ^６’は上記で定義された基Ｒ^６、またはＲ^６へ変換可能な基であり、Ｒ’は上記で定義された基Ｒ、またはＲへ変換可能な基であり、Ｑは上記で定義された通りであり、Ｚはブロモ、ヨード、クロロまたはトリフレートなどの脱離基である）
の化合物をパラジウムまたは銅触媒（ＶＩＩ）で処理して分子内環化を果たすことを含む。 In a further aspect, the present invention provides a general method (C) for preparing a compound of formula (I), the method comprising:
Formula (VI):

Wherein R ^{6 ′} is a group R ⁶ defined above or a group convertible to R ⁶ , R ′ is a group R defined above or a group convertible to R, and Q Is as defined above and Z is a leaving group such as bromo, iodo, chloro or triflate)
And treating the compound with palladium or copper catalyst (VII) to effect intramolecular cyclization.

  This cyclization reaction is carried out using various palladium or copper reagents as described in the literature (JACS, 2003, 125, 6653, Tet. Lett., 2004, 45, 8535 or JACS, 2002, 124, 7421). Can be used.

  It is believed that the compound of formula (VI) may be a pure cis or trans isomer, or a mixture of isomers. If necessary, separation of pure cis and trans isomers can be carried out by chromatography or crystallization after intramolecular cyclization.

の化合物と式（ＩＸ）：

（式中、Ｒ^６’は上記で定義された基Ｒ^６、またはＲ^６へ変換可能な基であり、Ｒ’は上記で定義された基Ｒ、またはＲへ変換可能な基であり、Ｑは上記で定義された通りであり、Ｒ^ａはＣ_１−５アルキル基である）
の化合物をカップリングさせることを含む。 In a further aspect, the present invention provides a general method (D) for preparing a compound of formula (I), the method comprising:
Formula (VIII):

And a compound of formula (IX):

Wherein R ^{6 ′} is a group R ⁶ defined above or a group convertible to R ⁶ , R ′ is a group R defined above or a group convertible to R, and Q Is as defined above and R ^a is a C _1-5 alkyl group)
Coupling the compound.

  This condensation and cyclization reaction is carried out under reaction conditions similar to those described in the literature for similar methods (see, eg, US Pat. No. 3,161,645) (eg, heated in an inert solvent such as xylene). Once done, the piperidine double bond can then be reduced using, for example, catalytic hydrogenation over palladium or Raney nickel.

  It is believed that the compound of formula (IX) may be a pure cis or trans isomer, or a mixture of isomers. If necessary, separation of pure cis and trans isomers can be carried out by chromatography or crystallization after intramolecular cyclization.

（式中、Ｒ^６’は上記で定義された基Ｒ^６、またはＲ^６へ変換可能な基であり、Ｒ’は上記で定義された基Ｒ、またはＲへ変換可能な基であり、Ｑは上記で定義された通りである）
の化合物とアジ化ジフェニルホスホリルまたはその他の試薬／試薬の組合せと反応させて化合物（Ｘ）のクルチウス転位を果たし、その後、分子内環化を行うことを含む。 In a further aspect, the present invention provides a general method (E) for preparing a compound of formula (I), the method comprising:
Formula (X):

Wherein R ^{6 ′} is a group R ⁶ defined above or a group convertible to R ⁶ , R ′ is a group R defined above or a group convertible to R, and Q Is as defined above)
Reaction of the compound with diphenylphosphoryl azide or other reagents / reagent combinations to effect the Curtius rearrangement of compound (X) followed by intramolecular cyclization.

  The Curtius rearrangement is generally performed by mixing the two reactants in an inert solvent such as toluene, optionally with heating.

  It is believed that the compound of formula (X) may be a pure cis or trans isomer, or a mixture of isomers. If necessary, separation of pure cis and trans isomers can be carried out by chromatography or crystallization after intramolecular cyclization.

の化合物と式（ＸＩＩ）：

（式中、Ｒ^６’は上記で定義された基Ｒ^６、またはＲ^６へ変換可能な基であり、Ｒ’は上記で定義された基Ｒ、またはＲへ変換可能な基であり、Ｑは上記で定義された通りであり、Ｚはヒドロキシまたはクロロ、ブロモまたはヨードもしくはアルキル／アリールスルホネートなどの脱離基である）
の化合物をカップリングさせることを含む。 In a further aspect, the present invention provides a general method (F) for preparing a compound of formula (I), which method is represented by formula (XI):

And a compound of formula (XII):

Wherein R ^{6 ′} is a group R ⁶ defined above or a group convertible to R ⁶ , R ′ is a group R defined above or a group convertible to R, and Q Is as defined above and Z is a leaving group such as hydroxy or chloro, bromo or iodo or alkyl / aryl sulfonate)
Coupling the compound.

  This alkylation reaction can be carried out under conventional alkylation (Z = leaving group) or Mitsunobu reaction (Z = OH) conditions. When conventional alkylation conditions are used, the benzimidazolone intermediate (XI) is deprotonated with a base such as sodium hydride in an inert solvent such as dimethylformamide and then optionally alkylated with heating. It can be treated with reagent (XII). The (XII) Mitsunobu reaction with Z = OH can be carried out at room temperature in an inert solvent such as dichloromethane or tetrahydrofuran under standard conditions such as triphenylphosphine and diethyl azodicarboxylate.

  It is believed that the compound of formula (X) may be a pure cis or trans isomer, or a mixture of isomers. If necessary, separation of pure cis and trans isomers can be carried out by chromatography or crystallization after intramolecular cyclization.

Conversion from R ^{6 ′} to R ⁶ or intramolecular conversion of R ⁶ can be performed as shown below.

For example, when R ^{6 ′} is a halogen, it can be converted to an alkoxy, trifluoromethyl, or methylsulfonyl group by copper catalysis with an alcohol, methylfluorosulfonyl (difluoro) acetate, or sodium methanesulfinate, respectively. . It can also be converted to an alkyl group with an organometallic reagent such as, for example, an alkylstannane.

In another example, when R ^{6 ′} is hydroxy, it is converted to alkoxy by reaction with an alkyl halide or sulfonate, or to trifluoromethoxy by conversion to xanthate followed by oxidation in the presence of fluoride ions. can do.

As a further example, when R ^{6 ′} is methyl, it can be converted to trifluoromethyl by displacing the introduced halogen with fluoride after chlorination or bromination.

  The conversion from R 'to R or the intramolecular conversion of R can be performed as follows.

For example, when R ′ is benzyl, the benzyl group can be removed using standard methodologies such as, for example, catalytic hydrogenation on palladium carbon to give the alcohol. Alkylation of the resulting alcohol with a strong base such as sodium hydride and a C _1-6 alkylating agent such as methyl iodide or ethyl iodide or propyl iodide provides the desired product. It may be necessary to protect the NH functionality present in the molecule.

  As another example, when R is methyl, the methyl group can be removed by treatment with a dealkylating agent such as boron tribromide to give an alcohol intermediate, similar to that described above. Can be alkylated. Alternatively, the alcohol intermediate can be converted to R, which is trifluoromethoxy, by conversion to xanthate and subsequent oxidation in the presence of fluoride ions.

  Compounds of formula (II) are generally known in the literature or can be prepared by a range of different methods, for example:

(A) ortho - fluoro or ortho - in chloronitrobenzene intermediate (XIII) amine (XIV) (wherein, R ^{6 'is} a group defined ^{R 6} or a group convertible to ^{R 6,} above, P Represents a nitrogen protecting group such as Boc, acetyl, trifluoroacetyl, ethoxycarbonyl, benzyloxycarbonyl, etc.) to give (XXIII), then the nitro group is reduced and phosgene or phosgene equivalent is used. Cyclize and deprotect the piperidine nitrogen using standard literature conditions (Scheme 1).
Scheme 1

  Compounds of formula (XIII) are commercially available or can be prepared by standard methodology. Compound (XIV) where P = Boc is commercially available.

(B) Metal catalyzed cyclization of intermediate (XV) followed by piperidine nitrogen deprotection (where R ^{6 ′} is a group R ⁶ as defined above or a group convertible to R ⁶ And P represents a nitrogen protecting group such as Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl, and Z represents a leaving group such as bromo, iodo, chloro or triflate). Reaction conditions for metal catalyzed cyclization are summarized in Method C. Urea (XV) can be produced using any of the conventional methods for urea formation, as shown in Scheme 2. The starting materials for this process are either commercially available or can be prepared using standard methodologies.
Scheme 2

(C) Intermediate (XVI) (wherein R ^{6 ′} is the group R ⁶ defined above or a group convertible to R ⁶ , and P is, for example, Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl) Of a nitrogen protecting group such as R ^b represents H or a C _1-5 alkyl group such as methyl or ethyl), followed by intramolecular cyclization and piperidine nitrogen (Scheme 3). Anthranilic acid or ester starting material (XVII) is commercially available or can be prepared by standard methodologies. Piperidone starting materials (P = Boc or benzyl) are commercially available. This Curtius rearrangement can be performed using the conditions described in Method E.
Scheme 3.

(D) Orthophenylenediamine (VIII) and 3-alkoxycarbonyl-4-piperidone (XX) (wherein R ^{6 ′} is a group R ⁶ as defined above) by heating at high temperature in an inert solvent. Or a group that can be converted to R ⁶ , P represents a nitrogen protecting group such as Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl, and R ^b is a C _1-5 alkyl group) (Scheme 4) To give the tetrahydropyridine intermediate (XXI). Hydrogenation of the double bond and deprotection of the piperidine nitrogen can be carried out separately or in parallel depending on the exact nature of the protecting group P to give the desired product (II). Compounds of formula (VIII) are commercially available or can be prepared by standard methodology. Compounds of formula (XX) are commercially available or can be prepared by standard methodology.
Scheme 4.

(E) N-protected 4-piperidone (XVIII) and orthonitroaniline (XXII), for example using sodium triacetoxyborohydride, wherein R ^{6 ′} is converted to the group R ⁶ as defined above, or R ⁶ Reductive alkylation of possible groups, P representing nitrogen protecting groups such as Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl, etc., to give intermediate (XXIII). After reduction of the nitro group, cyclization and deprotection are performed as described above to give the desired product (II) (Scheme 5). Compounds of formula (XXII) and (XVIII) are commercially available or can be prepared by standard methodologies.
Scheme 5.

(F) A nitrobenzene compound (XXIV) optionally substituted with amine (XIV) (wherein R ^{6 ′} is a group R ⁶ defined above or a group convertible to R ⁶ , and P is, for example, Boc, A metal catalyzed reaction (representing a nitrogen protecting group such as acetyl, trifluoroacetyl, benzyloxycarbonyl, Z representing a leaving group such as bromo, iodo, chloro or triflate) (Scheme 6). By this method, an intermediate of formula (XXIII) is obtained, and the subsequent reaction is the same as in Scheme 5. Compounds of formula (XXIV) are commercially available or can be prepared by known methodologies. Compound (XIV) where P = Boc is commercially available.
Scheme 6.

(G) Amine (XIV) and protected aniline (XXV) (wherein R ^{6 ′} is a group R ⁶ defined above or a group convertible to R ⁶ , and P and P ′ are independently, for example, Boc Represents a nitrogen protecting group such as acetyl, trifluoroacetyl, benzyloxycarbonyl, and Z represents a leaving group such as bromo, iodo, chloro or triflate) by an intermediate ( XXVI) is obtained (Scheme 7). Deprotection of the aniline followed by the same series of reactions as in Scheme 6 yields the desired intermediate (II). Compounds of formula (XXV) are commercially available or can be prepared by known methodologies (eg, orthohalogenation to an optionally protected aniline group). Compound (XIV) where P = Boc is commercially available.
Scheme 7

  Compounds of formula (III) can be prepared by standard literature methodologies.

The compound of formula (IV) can be prepared by several different methods as follows.
(H) An ortho-fluoro or ortho-chloronitrobenzene intermediate (XIII) is converted to an amine (XXVII) (wherein R ^{6 ′} is a group that can be converted to the group R ⁶ or R ⁶ defined above; 'Is a group R as defined above or a group convertible to R, Q is as defined above) to give compound (XXVIII), for example on palladium or Raney nickel The nitro group is reduced using standard conditions such as hydrogenation of (Scheme 8). Compounds of formula (XIII) are commercially available or can be prepared by standard methodology. It is contemplated that separation of the cis and trans isomers may be performed at any suitable stage of the synthesis.
Scheme 8

(I) Amine (XXVII) and ortho-substituted nitrobenzene (XXIX) (wherein R ^{6 ′} is a group R ⁶ defined above or a group convertible to R ⁶ , and R ′ is defined above) The reaction catalyzed by the group R, or a group convertible to R, Q is as defined above) affords compound (XXVIII) (Scheme 9), which is then shown in Scheme 8 Perform the same reaction as Compounds of formula (XXIX) are commercially available or can be prepared by standard methodologies. It is contemplated that separation of the cis and trans isomers may be performed at any suitable stage of the synthesis.
Scheme 9

(J) Amine (XXVII) and protected aniline derivative (XXV) (wherein R ^{6 ′} is a group R ⁶ defined above or a group convertible to R ⁶ , and R ′ is defined above) Group R or a group convertible to R, Q is as defined above and P ′ represents a nitrogen protecting group such as acetyl, trifluoroacetyl, Boc, phthalimide, etc.) The compound (XXXI) is obtained by the reaction (Scheme 10), and then the aniline group is deprotected. Compounds of formula (XXV) are commercially available or can be prepared by standard methodology. It is contemplated that separation of the cis and trans isomers may be performed at any suitable stage of the synthesis.
Scheme 10

(K) Piperidone (XXXII) of orthonitroaniline (XXII), for example using sodium triacetoxyborohydride in dichloroethane, wherein R ^{6 ′} is converted to the group R ⁶ or R ⁶ as defined above. R ′ is a group R as defined above, or a group convertible to R, Q is as defined above), and reductive alkylation with intermediate (XXVIII) (Scheme 11). For example, reduction of the nitro group with palladium on carbon or Raney nickel provides the desired intermediate (IV). It is contemplated that separation of the cis and trans isomers may be performed at any suitable stage of the synthesis.
Scheme 11

  Compounds of formula (V) are commercially available, for example carbonyldiimidazole, phosgene, phosgene in toluene, diphosgene, triphosgene, phenyl chloroformate, diethyl carbonate.

Compounds of formula (VI) can be prepared by a variety of methods, for example, urea formation can be achieved by the following, as shown in Scheme 12.
Combine the two amines (XXXIV) and (XXVII) with phosgene or phosgene equivalents using standard conditions (phosgene equivalents include carbonyldiimidazole, diphosgene, triphosgene, phenyl chloroformate)
• Reacting amine (XXVII) with isocyanate (XXXV) • Reacting amine (XXXIV) with isocyanate (XXXVI) Both isocyanates are prepared using standard methodology for the formation of isocyanates from the corresponding amines can do. It is contemplated that separation of the cis and trans isomers may be performed at any suitable stage of the synthesis.
Scheme 12.

  Palladium and copper catalysts (VII) are commercially available or can be prepared as described in the literature (see method C reference).

  Compounds of formula (VIII) are commercially available or can be prepared by known literature routes, for example by reduction of mono- or dinitrobenzene precursors.

  Compounds of formula (IX) can be prepared by reductive alkylation of 3-alkoxycarbonyl-4-piperidone with cyclohexanone (III).

Compounds of formula (X) can be prepared as shown in Scheme 13. Reductive alkylation of anthranilic acid or ester (XVII) with ketone (XXXII) is followed by hydrolysis of the ester group, if appropriate. It is contemplated that separation of the cis and trans isomers may be performed at any suitable stage of the synthesis.
Scheme 13.

  Compounds of formula (XI) are commercially available or can be prepared by literature methods.

Compounds of formula (XII) where Q = H are reduced with ketone (III) as shown in Scheme 14 where (XXXVII) (wherein Z ′ represents Z or a group convertible to Z) Can be prepared by mechanical alkylation. Conversion of the Z ′ hydroxy group to Z = chloro or bromo can be accomplished using standard methodologies such as treatment with thionyl chloride or triphenylphosphine / carbon tetrabromide. It is contemplated that separation of the cis and trans isomers may be performed at any suitable stage of the synthesis.
Scheme 14

Compound (XXVII) where Q = H can be prepared as shown in Scheme 15. For example, reductive alkylation of commercially available amine (XXXVIII) with cyclohexanone (III) using sodium triacetoxyborohydride in dichloroethane yielded intermediate (XXXIX), which was diluted with HCl in ethanol or trifluoroacetic acid. To deprotect to give the primary amine (XXVII). It is contemplated that separation of the cis and trans isomers may be performed at any suitable stage of the synthesis.
Scheme 15

  Compound (XXVII) wherein Q = alkyl can be prepared in the same manner as Method A2, followed by deprotection.

Alternatively, compound (XXVII) where Q = H can be prepared as shown in Scheme 16. For example, by reductive amination of cyclohexanone (III) using an ammonia solution under catalytic hydrogenation conditions to obtain an intermediate amine (XI), which is reacted with a quaternary piperidine salt (XII). Can be converted to piperidinone (XIII). For example, primary amines (XXVII) can be obtained by reductive amination using ammonia and catalytic hydrogenation. It is contemplated that separation of the cis and trans isomers may be performed at any suitable stage of the synthesis.
Scheme 16

Selective preparation of the cis and trans isomers of compound (XXVII) where Q = H can be carried out by the method shown in Scheme 17 for the trans isomer. Commercially available amine (XLIII) is first N-protected by, for example, incorporation into a phthalimide ring to give (XLIV), after which the hydroxyl function is converted to a silyl protecting group such as tert-butyldimethylsilyl to convert (XIV) This is treated with the appropriate aldehyde or ketone in the presence of triethylsilane and bismuth tribromide to give (XLVI) and, after deprotection, the intermediate amine (XLVII). The amine (XLVII) is converted to piperidinone (XLVIII) by reaction with a quaternary piperidine salt (XII), followed by reductive amination using, for example, ammonia and catalytic hydrogenation to produce a primary amine (XXVII). )
Scheme 17

  The cis isomer of compound (XXVII) can be prepared from the appropriate cis amine (XLIII) by similar procedures.

Selective preparation of the trans isomer of compound (XXVII) where Q = Me is shown in Scheme 18. Protection of a suitable ester (XIIX) of 4-hydroxycyclohexanecarboxylic acid such as methyl or ethyl as a silyl ether such as tert-butyldimethylsilyl gives (L), in the presence of triethylsilane and bismuth tribromide, Treatment with a suitable aldehyde or ketone provides the ether (LI). After acid hydrolysis (LII), alkylation is performed using a base such as lithium diisopropylamide with iodomethane to give a mixture of cis and trans 1-methylcyclohexanecarboxylic acid (LIIII). The trans isomer (LIV) can be obtained by selective hydrolysis of these products, for example, by converting the mixture to the acid chloride with thionyl chloride and then treating with an aqueous weak base such as sodium bicarbonate solution. Can be separated. This acid can be converted to isocyanate (IV) by, for example, high temperature Curtius rearrangement of an intermediate azide prepared using diphenylphosphoryl azide, followed by hydrolysis of the isocyanate to amine (IVI) under acidic conditions. Can do. The amine (LVI) is converted to piperidinone (LVII) by reaction with a quaternary piperidine salt (XLI) followed by a reductive amination using, for example, ammonia and catalytic hydrogenation to produce a primary amine (XXVII). )
Scheme 18

The cis isomer of (XXVII) where Q = Me can be obtained as shown in Scheme 19. This acid mixture (LIII) is converted to a mixture of isocyanates (LVIII) by Curtius rearrangement of an intermediate azide prepared, for example, using diphenylphosphoryl azide, at high temperature. The cis isomer (LIX) is isolated from this mixture by chromatographic separation and then through intermediates (LX) and (LXI) using a procedure similar to that shown for the trans isomer in Scheme 17. Can be converted to amine (XXVII).
Scheme 19

The compounds of the present invention are M ₁ receptor agonists. Selective M ₁ receptor agonists are positive and cognitive symptoms of psychotic disorders such as schizophrenia, schizophrenia-affective disorder, schizophrenia-like illness, mental depression, mania, acute mania, delusions and delusional disorders, And is said to be useful in ameliorating cognitive impairment, including memory impairment such as Alzheimer's disease without peripheral cholinergic side effects mediated primarily by M ₂ and M ₃ receptors. M ₁ receptor agonists also to provide enhanced treatment of psychotic disorders, mood stabilizers, antidepressants, anxiolytics, other standard and non such drugs and nootropics for extrapyramidal side effects It may be suitable for combination with typical antipsychotics and other active agents.

  Thus, in a further aspect, the present invention provides a compound of formula (I) as hereinbefore described or a salt or solvate thereof for use in therapy.

In another aspect, the present invention provides a compound of formula (I) or a salt or solvate thereof for use in the treatment of a condition requiring a muscarinic M ₁ receptor stimulatory effect.

  The terms used to describe the indications used herein are the Diagnostic and Statistical Manual of Mental published in the American Psychiatric Association (DSM-IV) and / or the International Classification of Diseases, 10th Edition (ICD-10). Disorders, 4th edition. Various subtypes of the disorders described herein are also considered part of this invention. The numbers in parentheses after the diseases listed below represent the DSM-IV classification code.

  Within the scope of the present invention, psychotic disorders are delusional (295.30), dismantled (295.10), tension (295.20), indistinguishable (295.90) and residual ( 295.60) Schizophrenia including subtypes; Schizophrenia-like disorder (295.40); Schizophrenia including bipolar and depressive subtypes (295.70); Color delusional type, paranoid type, epilepsy Delusional disorders including delusional, delusional, physical delusional, mixed and indistinguishable subtypes (297.1); short-term psychotic disorders (298.8); shared psychotic disorders (297.3); Psychiatric disorders not due to general physical disease, including subtypes with delusions and hallucinations; Substance-induced psychotic disorders, including subtypes with delusions (293.81) and hallucinations (293.82); and not elsewhere classified Includes psychotic disorders (298.9).

Other symptoms that require muscarinic M ₁ receptor stimulatory action for its treatment include depression and mood disorders including major depression episodes, mania episodes, mixed episodes and hypomania episodes; major depression disorders, thymic abnormalities Depression (300.4), depressive disorders including other unclassified depressive disorders (311); bipolar I disorder, bipolar II disorder (recurrent major depression episode with hypomania episode) (296.89), Bipolar disorders including cardiovascular disease (301.13) and unclassified bipolar disorder (296.80); including subtypes with depression characteristics, major depression-like episodes, mania characteristics and mixed characteristics Mood disorders due to physical disease (293.83), substance-induced mood disorders (including subtypes with depression characteristics, major depression-like episodes, depression characteristics and mixed characteristics) Other mood disorders including mood disorders not classified elsewhere (296.90); social anxiety disorder, panic attacks, agoraphobia, panic disorder, agoraphobia without history of panic disorder (300.22), animal type Specific phobia (300.29), social phobia (300.23), obsessive compulsive disorder (300.3), including natural environment type, blood-injection-trauma type, situation type and other subtypes Post-traumatic stress disorder (309.81), acute stress disorder (308.3), generalized anxiety disorder (300.02), general physical disease anxiety disorder (293.84), substance-induced anxiety disorder and others Anxiety disorders, including anxiety disorders not classified as 300.00;
Substance use disorders such as substance dependence, substance craving and substance abuse; substance addiction, substance withdrawal symptoms, substance-induced delirium, substance-induced persistent dementia, substance-induced persistent amnesia disorder, substance-induced psychotic disorder, Substance-induced disorders such as substance-induced mood disorder, substance-induced anxiety disorder, substance-induced dysfunction, substance-induced sleep disorder, and hallucinogen persistent perception disorder (flashback); alcoholism (303.90) Alcohol abuse (305.00), alcohol addiction (303.00), alcohol withdrawal symptoms (291.81), alcohol addiction delirium, alcohol withdrawal delirium, alcohol-induced persistent dementia, alcohol-induced persistent amnesia, Alcohol-induced psychotic disorder, alcohol-induced mood disorder, alcohol-induced anxiety disorder, alcohol-induced dysfunction Alcohol-related disorders such as alcohol-induced sleep disorders and other unclassified alcohol-related disorders (291.9); amphetamine dependence (304.40), amphetamine abuse (305.70), amphetamine addiction (292.89), amphetamine Withdrawal symptoms (292.0), amphetamine intoxication delirium, amphetamine-induced psychotic disorder, amphetamine-induced mood disorder, amphetamine-induced anxiety disorder, amphetamine-induced dysfunction, amphetamine-induced sleep disorder and unclassified amphetamine-related Amphetamine (or amphetamine-like) related disorders such as disorders (292.9); caffeine addiction (305.90), caffeine-induced anxiety disorder, caffeine-induced sleep disorder and caffeine-related not otherwise classified Caffeine-related disorders such as harm (292.9); cannabis dependence (304.30), cannabis abuse (305.20), cannabis poisoning (292.89), cannabis poisoning delirium, cannabis-induced psychotic disorders, cannabis Cannabis-related disorders such as induced anxiety disorder and other unclassified cannabis-related disorders (292.9); cocaine addiction (304.20), cocaine abuse (305.60), cocaine addiction (292.89), cocaine withdrawal Symptoms (292.0), cocaine addiction delirium, cocaine-induced psychotic disorder, cocaine-induced mood disorder, cocaine-induced anxiety disorder, cocaine-induced dysfunction, cocaine-induced sleep disorder and other cocaine-related disorders not classified Cocaine-related disorders such as (292.9); hallucinogen dependence (304.50), hallucinogen abuse (305.30), hallucinogen poisoning (29 2.89), hallucinogen persistent sensory impairment (flashback) (292.89), hallucinogen poisoning delirium, hallucinogen-induced psychotic disorder, hallucinogen-induced mood disorder, hallucinogen-induced anxiety disorder and others Hallucinogen-related disorders such as unclassified hallucinogen-related disorders (292.9); inhalant dependence (304.60), inhalant abuse (305.90), inhalant poisoning (292.89), inhalant intoxication delirium , Inhalant-related persistent dementia, inhalant-induced psychotic disorders, inhalant-induced mood disorders, inhalant-induced anxiety disorders, and other inhalant-related disorders not classified elsewhere (292.9) Disorders; Nicotine-related disorders such as nicotine dependence (305.1), nicotine withdrawal symptoms (292.0) and nicotine-related disorders not otherwise classified (292.9); opioid dependence (304.00) Opioid abuse (305.50), opioid addiction (292.89), opioid withdrawal symptoms (292.0), opioid addiction delirium, opioid-induced psychotic disorder, opioid-induced mood disorder, opioid-induced dysfunction, opioid Opioid-related disorders such as induced sleep disorders and opioid-related disorders not otherwise classified (292.9); phencyclidine dependence (304.60), phencyclidine abuse (305.90), phencyclidine addiction (292) .89), phencyclidine intoxication delirium, phencyclidine-induced psychotic disorder, phencyclidine-induced mood disorder, phencyclidine-induced anxiety disorder and other phencyclidine-related disorders (292.9) Related to phencyclidine (or phencyclidine-like) Harm; Sedative, hypnotic, or anxiolytic dependence (304.10), sedative, hypnotic, or anxiolytic abuse (305.40), sedative, hypnotic, or anxiolytic addiction (292) .89), sedative, hypnotic, or anxiolytic withdrawal symptoms (292.0), sedative, hypnotic, or anxiolytic addiction delirium, sedative, hypnotic, or anxiolytic withdrawal delirium, sedative , Sedatives, hypnotics, or anxiolytics persistent amnesia, sedatives, hypnotics, or anxiolytic-induced psychotic disorders, sedatives, hypnotics, Or anxiolytic-induced mood disorder, sedative, hypnotic, or anxiolytic-induced anxiety disorder sedative, hypnotic, or anxiolytic-induced dysfunction, sedative, hypnotic, or anxiolytic Sexual sleep disorders and sedatives, hypnotics, or otherwise not classified Sedatives, hypnotics, or anxiolytic-related disorders such as anxiolytic-related disorders (292.9); multi-substance-related disorders such as multi-substance dependence (304.80); and anabolic steroids, nitrates And substance-related disorders, including other (or unknown) substance-related disorders such as nitrogen dioxide;
Primary insomnia (307.42), primary hypersomnia (307.44), sleep seizures (347), breathing-related sleep disorders (780.59), 24-hour rhythm sleep disorders (307.45) And primary sleep disorders such as sleep disorders such as sleep disorders not classified elsewhere (307.47); nightmare disorder (307.47), sleep phobia disorder (307.46), sleepwalking (307.46) And primary sleep disorders such as parasomnia (307.47), and other insomnia associated with other mental disorders (307.42) and other psychological disorders not classified elsewhere Sleep disorders associated with other mental disorders such as hypersomnia (307.44); sleep disorders due to general physical illness; and substance-induced sleep including insomnia, hypersomnia, concomitant sleep and mixed subtypes Sleep with disabilities Harm;
Anorexia nervosa (307.1) including restricted and non-tea-eating / excreting subtypes; bulimia nervosa (307.51) including excretory and non-excreting subtypes; obesity; obsessive compulsive eating disorder As well as eating disorders such as eating disorders not otherwise classified (307.50);
Childhood autism (299.00); attention deficit / hyperactivity disorder mixed type (314.01), attention deficit / hyperactivity disorder inattention dominant type (314.00), attention deficit / hyperactivity disorder Attention deficit / hyperactivity disorder, including subtypes of attention-deficit / hyperactivity disorder (314.9) and non-categorized attention-deficit / hyperactivity disorder (314.01); hyperactivity disorder; childhood-onset ( 321.81), behavioral disorders including adolescent onset (312.82) and age-onset (312.89) subtypes, rebellious behavioral disorders (313.81) and other categorical disruptive behavioral disorders Destructive behavioral disorders; as well as tic disorders such as Tourette's disorder (307.23);
Delusional personality disorder (301.0), schizophrenic personality disorder (301.20), schizophrenic personality disorder (301, 22), antisocial personality disorder (301.7), borderline personality disorder (301 83), acting personality disorder (301.50), self-loving personality disorder (301, 81), avoidable personality disorder (301.82), dependent personality disorder (301.6), compulsive personality disorder ( 301.4) and personality disorders that do not fall elsewhere (301.9) subtypes; and sexual desire disorders such as sexual desire disorder (302.71) and sexual aversion disorder (302.79); Sexual arousal disorders such as female sexual arousal disorder (302.72) and male erectile dysfunction (302.72); female orgasmic disorder (302.73), male orgasmic disorder (302.74) and premature ejaculation ( 302.75 Orgasmic disorders such as; sexual pain disorders such as sexual pain (302.76) and vaginal spasticity (306.51); sexual dysfunction not classified elsewhere (302.70); exposure (302.4), fetishism (302.81), pervertism (302.89), childhood love (302.2), sexual masochism (302.83), sexual sadism (302.84), clothes-inverted fetishism (302.3), Sexual libido, such as peeping fox (302.82) and unclassified libido (302.9); childhood gender identity disorder (302.6) and adolescent or adult gender identity disorder (302.85) Sexual dysfunction, including sexual dysfunction of the other; as well as sexual disorders not classified elsewhere (302.9).

  The compounds of formula (I) treat cognitive impairment itself and cognitive impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and mental states associated with cognitive impairment, and It may also be useful for enhancing cognition including both.

  Within the scope of the present invention, the term cognitive impairment means, for example, attention, orientation, learning impairment, memory (ie memory impairment, amnesia, memory loss disorder, transient global amnesia syndrome and memory impairment associated with aging) and Impaired cognitive function, including language function; stroke, Alzheimer's disease, Huntington's disease, Pick's disease, AIDS dementia or multiple cerebral infarction dementia, alcoholic dementia, hypothyroidism-related dementia, and cerebellar atrophy and muscle atrophy Cognitive impairment as a result of other dementia conditions such as dementia associated with other degenerative disorders such as lateral sclerosis; traumatic delirium or depression (fake) that can cause cognitive decline Dementia state), head trauma, age-related cognitive decline, stroke, neurodegeneration, drug state, neurotoxic, mild cognitive impairment, age-related cognitive impairment, cognitive impairment due to autism, Dow Other acute or subacute conditions such as syndrome, cognitive impairment associated with psychosis, and cognitive impairment associated with post-shock treatment; and motor disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and late-onset dyskinesia Including.

  The therapies of the invention can also be used as memory enhancers and / or cognitive enhancers in healthy humans without cognitive and / or memory deficits.

  In another aspect, the present invention provides a compound of formula (I) as hereinbefore described or a salt or solvate thereof for use in the treatment of a psychotic disorder. In one embodiment, the present invention provides a compound of formula (I) as hereinbefore described or a salt or solvate thereof for use in the treatment of schizophrenia.

  The present invention also provides a compound of formula (I) as hereinbefore described or a salt or solvate thereof for use in the treatment of cognitive impairment.

In another aspect, the present invention provides the use of a compound of formula (I) as hereinbefore described or a salt or solvate thereof in the manufacture of a medicament for the treatment of a condition requiring a stimulatory action of a muscarinic M ₁ receptor. provide.

  In another aspect, the present invention provides a compound of formula (I) as hereinbefore described or a salt or solvate thereof in the manufacture of a medicament for the treatment of a psychotic disorder. In one embodiment, the invention provides use in the manufacture of a compound of formula (I) as hereinbefore described or a salt or solvate thereof for the treatment of schizophrenia.

  The present invention also provides the use of a compound of formula (I) as hereinbefore described or a salt or solvate thereof in the manufacture of a medicament for the treatment of cognitive impairment.

In another aspect, the invention provides a method of treating a condition requiring a muscarinic M ₁ receptor stimulatory effect, said method comprising an effective amount of the above formula (I) in a mammal in need thereof. ) Or a salt or solvate thereof. In one embodiment, the mammal is a human.

  In another aspect, the invention provides a method of treating a psychotic disorder comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a salt or solvate thereof. A method of including is provided. In one embodiment, the present invention is a method of treating schizophrenia comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a salt or solvate thereof. Provide a way to include. In one embodiment, the mammal is a human.

  The present invention also provides a method of treating cognitive impairment, comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a salt or solvate thereof. . In one embodiment, the mammal is a human.

  Compounds of formula (I) and their salts and solvates thereof are used to provide improved treatment of psychotic disorders, typical and atypical antipsychotics, mood stabilizers, antidepressants, anxiolytics, extrapyramidal It may be suitable to combine with other active agents such as drugs for tract side effects and nootropics.

  The combination therapy of the present invention is administered, for example, as an adjunct. By auxiliary administration is meant coterminous or overlapping administration of each component in the form of separate pharmaceutical compositions or devices. This therapeutic regimen of two or more therapeutic agents is commonly referred to as adjunctive therapeutic administration in the art and herein, also known as additional therapeutic administration. The patient is an individual of the compound of formula (I) or a salt or solvate thereof and at least one antipsychotic, mood stabilizer, antidepressant, anxiolytic, drug for extrapyramidal side effects or nootropics However, any and all treatment regimes that receive a therapeutic administration or a common therapeutic administration with a common boundary are within the scope of the invention. In one embodiment of the adjunct therapeutic administration described herein, the patient is generally stabilized for a period of time with the therapeutic administration of one or more of those components before receiving the administration of another component. The compound of formula (I) or a salt or solvate thereof is administered with at least one antipsychotic agent, mood stabilizer, antidepressant, anxiolytic agent, a drug for extrapyramidal side effects or a nootropic agent. Can be administered to a patient as an adjunct therapeutic treatment, but the scope of the present invention is also within the scope of at least one type of patient receiving a compound of formula (I) or a salt or solvate thereof. Also included are adjuvant treatment with antipsychotics, mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects or nootropics.

  The combination therapies of the invention can also be administered simultaneously. Co-administration means that the individual components are in the form of a single pharmaceutical composition or device comprising or containing both components or together as separate compositions or devices each containing one component to be administered simultaneously. Refers to the treatment regimen administered. Combinations of separate components for such simultaneous combination can be provided in the form of a parts kit.

  Thus, in a further aspect, the present invention relates to the treatment of psychotic disorders by adjunct therapeutic administration of a compound of formula (I) or a salt or solvate thereof to a patient receiving therapeutic administration of at least one antipsychotic agent. Provide a method of treatment. In a further aspect, the invention provides a compound of formula (I) in the manufacture of a medicament for adjunct therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent Or use of a salt or solvate thereof. The present invention further provides a compound of formula (I) or a salt or solvate thereof for use in adjunct therapy for the treatment of psychotic disorders in patients receiving therapeutic administration of at least one antipsychotic drug Offer things.

  In a further aspect, the present invention provides a method of treating a psychotic disorder by adjunct therapeutic administration of at least one antipsychotic agent to a patient receiving therapeutic administration of a compound of formula (I) or a salt or solvate thereof. I will provide a. In a further aspect, the invention relates to the manufacture of a medicament for adjunct therapeutic administration for the treatment of psychotic disorders in a patient receiving therapeutic administration of a compound of formula (I) or a salt or solvate thereof. Provide use for at least one antipsychotic. The present invention further provides at least one antipsychotic agent for adjunct therapeutic administration for the treatment of psychotic disorders in patients receiving therapeutic administration of a compound of formula (I) or a salt or solvate thereof I will provide a.

  In a further aspect, the present invention provides a method of treating a psychotic disorder by simultaneous therapeutic administration of a compound of formula (I) or a salt or solvate thereof in combination with at least one antipsychotic agent. The present invention further provides the use of a combination of a compound of formula (I) or a salt or solvate thereof and at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. . The invention further provides the use of a compound of formula (I) or a salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The present invention further provides a compound of formula (I) or a salt thereof for use in simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides the use of at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration with a compound of formula (I) or a salt thereof in the treatment of a psychotic disorder.

  In a further aspect, the present invention comprises a first dosage form comprising a compound of formula (I) or a salt or solvate thereof and one or more additional dosage forms each comprising an antipsychotic for simultaneous therapeutic administration, A parts kit for use in the treatment of psychotic disorders is provided.

  In another aspect, the invention provides a patient receiving therapeutic administration of an active ingredient selected from the group consisting of mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics. Methods of treating psychotic disorders by adjunct therapeutic administration of the compounds of the present invention are provided.

  In a further aspect, the present invention relates to psychotic in patients receiving therapeutic administration of an active ingredient selected from the group consisting of mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics. There is provided the use of a compound of the invention in the manufacture of a medicament for adjunct therapeutic administration for the treatment of disorders.

  The present invention also treats psychotic disorders in patients receiving therapeutic administration of an active ingredient selected from the group consisting of mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics. There is provided the use of a compound of the invention in adjunct therapeutic administration for the purpose of

  The present invention further provides for the treatment of psychotic disorders in patients receiving therapeutic administration of an active ingredient selected from the group consisting of mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics. There is provided the use of a compound of the invention for use in adjunct therapeutic administration.

  In a further aspect, the present invention is selected from the group consisting of mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics to patients receiving therapeutic administration of compounds of the present invention. A method of treating a psychotic disorder by adjunct therapeutic administration of the active ingredient is provided.

  In a further aspect, the present invention provides a mood stabilizer, antidepressant, anti-antigen in the manufacture of a medicament for adjunct therapeutic administration for the treatment of psychotic disorders in a patient receiving therapeutic administration of a compound of the invention. The use of an active ingredient selected from the group consisting of anxiety drugs, drugs for extrapyramidal side effects and nootropics is provided.

  The invention also provides mood stabilizers, antidepressants, anxiolytics, extrapyramidal systems for adjunct therapy administration for the treatment of psychotic disorders in patients receiving therapeutic administration of compounds of the invention. Use of an active ingredient selected from the group consisting of drugs and nootropics for side effects is provided.

  In a further aspect, the present invention provides for co-therapeutic administration of a compound of the present invention in combination with an active ingredient selected from the group consisting of mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics Provides a method for treating psychotic disorders.

  The present invention further includes from the compounds of the present invention and mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of psychotic disorders. Use of a combination of active ingredients selected from the group consisting of is provided.

  The invention is further selected from the group consisting of compounds of the invention and mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics for simultaneous therapeutic administration in the treatment of psychotic disorders Use of a combination of active ingredients is provided.

  The present invention is further for simultaneous therapeutic administration with an active ingredient selected from the group consisting of mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics in the treatment of psychotic disorders. There is provided the use of a compound of the invention in the manufacture of a medicament.

  The present invention is further for simultaneous therapeutic administration with an active ingredient selected from the group consisting of mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics in the treatment of psychotic disorders. Of the compounds of the present invention.

  The present invention further provides for the simultaneous therapeutic administration of an active ingredient selected from the group consisting of mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics in the treatment of psychotic disorders. A compound of the invention for use in is provided.

  The present invention further provides mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics in the manufacture of a medicament for simultaneous therapeutic administration with a compound of the present invention in the treatment of psychotic disorders. Use of an active ingredient selected from the group consisting of:

  The invention further comprises the group consisting of mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and nootropics for simultaneous therapeutic administration with compounds of the invention in the treatment of psychotic disorders. Provides use of the active ingredient selected.

  In a further aspect, the present invention provides a first dosage form comprising a compound of the present invention and a mood stabilizer, an antidepressant, an anxiolytic, an agent for extrapyramidal side effects and a nootropic for simultaneous therapeutic administration, respectively. A kit of parts for use in the treatment of a psychotic disorder comprising one or more additional dosage forms comprising an active ingredient selected from the group consisting of:

  In one embodiment, the patient is a human.

  Examples of antipsychotics that may be useful in the present invention include, but are not limited to: sodium channel blockers; mixed 5HT / dopamine receptor antagonists; mGluR5 positive modulators; D3 antagonists; 5HT6 antagonists; Glycine transporter GlyT1 inhibitor; D2 partial agonist / D3 antagonist / H3 antagonist; AMPA modulator; NK3 antagonists such as osanetant and talnetant; atypical antipsychotics such as clozapine, olanzapine, Risperidone, quetiapine, aripiprazole, ziprasidone and amisulpride; butyrophenones such as haloperidol, pimozide, and droperidol; chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fu Phenothiazines such as phenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes such as thiothixene and chlorprothixene; thienobenzodiazepine; dibenzodiazepine; benzisoxazole; dibenzothiazepine; imidazolidinone; Examples include isothiazolyl piperazine; triazines such as lamotrigine; dibenzoxazepines such as loxapine; dihydroindolones such as morindon; aripiprazole; and derivatives thereof having antipsychotic activity.

  Examples of selected antipsychotic drug names and suppliers that may be suitable for use in the present invention are as follows: Clozapine (trade name CLOZARIL® from Mylan, Zenith Goldline, UDL, Novartis) Olanzapine (available under the trade name ZYPRXA® from Lilly; ziprasidone (available under the trade name GEODON® from Pfizer); risperidone (trade name RISPERDAL (available from Janssen) Quetiapine fumarate (available under the trade name SEROQUEL®) from AstraZeneca; Sertindole (available under the trade name SERLECT®); Amisulpride ( Available from Sanofi-Synthelabo under the trade name SOLION®); Haloperido (Available under the trade name HOLDOL® from Ortho-McNeil); haloperidol decanoate (available under the trade name HOLDOL decanoate®); haloperidol lactate (trade names HARDOL® and INTENTOL) Chlorpromazine (available from SmithKline Beecham (GSK) under the trade name THORAZINE®; fluphenazine (from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena) Available under the trade name PROLIXIN®; fluphenazine decanoate (available under the trade name PROLIXIN decanoate®); fluphenazine enanthate (available under the trade name PROLIXIN®) Yes); full hydrochloric acid Phenazine (available under the trade name PROLIXIN®); thiothixene (available under the trade name NAVANE® from Pfizer); thiothixene hydrochloride (available under the trade name NAVINE®) ); Trifluoperazine (10- [3- (4-methyl-1-piperazinyl) propyl] -2- (trifluoromethyl) phenothiazine dihydrochloride, available from SmithKline Beckman under the trade name STELAZINE® Perphenazine (available under the trade name TRILAFON® from Schering); perphenazine hydrochloride and amitriptyline hydrochloride (available under the trade name ETRAFON TRILAFON®); thioridazine (Novartis, Roxane, HiTech , Teva, and Alpharma trade name MELLLAR Morindon (available under the trade name MOBAN (R) from Endo); Morindon hydrochloride (available under the trade name MOBAN (R)); Loxapine ( Available from Watson under the trade name LOXITANE®; Loxapine hydrochloride (available under the trade name LOXITANE®); and Loxapine succinate (available under the trade name LOXITANE®) ). In addition, benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®)) may be used.

  Other suitable antipsychotics include promazine (available under the trade name SPARINE®), triflurpromazine (available under the trade name VESPRIN®), chlorpro Thixene (available under the trade name TARACTAN®), droperidol (available under the trade name INAPSINE®), acetophenazine (available under the trade name TINDAL®), Prochlorperazine (available under the trade name COMPAZINE (registered trademark)), Methotrimeprazine (available under the trade name NOZINAN (registered trademark)), Pipothiazine (available under the trade name PIPOTRIL (registered trademark)) ), Iloperidone, pimozide and flupentixol

  Antipsychotics listed above by trade name can also be obtained from other suppliers under different trade names.

  In one further aspect of the invention, suitable antipsychotics include olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone, talnetant and osanetant.

  Mood stabilizers that may be used in the therapy of the present invention include lithium, sodium valproate / valproic acid / divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, oxcarbazepine and tiagabine.

  Antidepressants that may be used in the therapy of the present invention include serotonin antagonists, CRF-1 antagonists, Cox-2 inhibitors / SSRI dual antagonists; dopamine / noradrenaline / serotonin triple reuptake inhibitors; NK1 antagonists; NK1 and NK2 dual antagonists; NK1 / SSRI dual antagonists; NK2 antagonists; serotonin agonists (such as lauorcin, yohimbine and metoclopramide); serotonin reuptake inhibitors (citalopram, escitalopram, fluoxetine, fluvoxamine, femoxetine, indalpin, dimerzine, Dual serotonin / noradrenaline reuptake inhibitors (eg venlafaxine, reboxetine, duloxetine and milnacipran); norad Narine reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline, and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine, and tranylcypramine) 5HT3 antagonists (such as ondansetron and granisetron); and others (such as bupropion, amineptin, radafaxin, mianserin, mirtazapine, nefazodone, and trazodone).

  Anti-anxiety agents that may be used in the therapy of the present invention include V1b antagonists, 5HT7 antagonists and benzodiazepines such as alprazolam and lorazepam.

  Agents for extrapyramidal side effects that may be used in the therapy of the present invention include anticholinergics (such as benztropine, biperidene, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopamine agonists. (Amantadine etc.).

  Nootropics that may be used in the therapy of the present invention include, for example, cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine), H3 antagonists and muscarinic M1 agonists (such as cevimeline).

  In one embodiment, the active ingredient used in combination with a compound of the invention is an atypical antipsychotic, such as clozapine, olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone or amisulpride.

  In one embodiment, the active ingredient used in combination with a compound of the invention is a typical antipsychotic such as chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixene, haloperidol, Flurpromazine, pimozide, droperidol, chlorprothixene, molindone or loxapine.

  In another embodiment, the active ingredient used in combination with the compound of the invention is a mood stabilizer such as lithium, sodium valproate / valproic acid / divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, oxycarbazepine Or Tiagabine.

  In another embodiment, the active ingredient used in combination with a compound of the present invention is an antidepressant, such as a serotonin agonist (such as laurucine, yohimbine or metoclopramide); a serotonin reuptake inhibitor (citalopram, escitalopram, fluoxetine, fluvoxamine, Femoxetine, indalpine, dimerzine, paroxetine or sertraline); dual serotonin / noradrenaline reuptake inhibitors (such as venlafaxine, reboxetine, duloxetine or milnacipran); noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (Such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline or trimipramine); monoamine oxidase inhibitors ( A or other (bupropion, amineptine, radafaxine, mianserin, mirtazapine, such as nefazodone or trazodone); Karubokisajido, moclobemide, etc. phenelzine or anthranilate Shipu lamin).

  In another embodiment, the active ingredient used in combination with a compound of the invention is an anxiolytic such as a benzodiazepine such as alprazolam or lorazepam.

  For pharmaceutical use, the compounds of the invention are usually administered as a standard pharmaceutical composition. The invention thus provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a salt or solvate thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be for use in the treatment of any of the conditions described herein.

  The compounds of formula (I) can be administered, for example, by oral administration, parenteral administration (eg intravenous administration), buccal administration, sublingual administration, nasal administration, rectal administration or transdermal administration and correspondingly adapted pharmaceutical compositions, etc. It can be administered in any conventional manner.

  The above-mentioned compounds of formula (I) and their salts or solvates when administered orally are formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges be able to.

  Liquid formulations generally consist of a suspension or solution of the compound or salt or solvate in a liquid carrier such as, for example, an aqueous solvent such as water, ethanol or glycerin, or a non-aqueous solvent such as polyethylene glycol or oil. The formulation may also contain a suspending agent, preservative, flavoring or coloring agent.

  A composition in the form of a tablet can be made using any suitable pharmaceutical carrier conventionally used to make solid formulations. Examples of such carriers are magnesium stearate, starch, lactose, sucrose and cellulose.

  Compositions in the form of capsules can be manufactured using conventional encapsulation procedures. For example, pellets containing the active ingredient are made using standard carriers and then filled into hard gelatin capsules or using any suitable pharmaceutical carrier such as aqueous gum, cellulose, silicate or oil. After the dispersion or suspension is prepared, the dispersion or suspension can be filled into gelatin soft capsules.

  A typical parenteral composition is a solution or suspension of a compound or salt or solvate in a sterile aqueous carrier or parenterally acceptable oil such as, for example, polyethylene glycol, polyvinyl pyrrolidone, lecithin, peanut oil or sesame oil. Consists of a turbid liquid. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent prior to administration.

  Compositions for nasal administration can be conveniently formulated as aerosols, drops, gels and powders. Aerosol formulations generally comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent, usually in a closed container that can take the form of a cartridge or refill for use with an atomizing device. Provided in sterile form as single or multiple doses. Alternatively, the sealed container may be a unit dispensing device such as a single dose nasal inhaler or an aerosol dispenser with a metering valve intended to be discarded once the contents of the container are used up. Where the dosage form comprises an aerosol dispenser, it comprises a propellant, which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage form may also take the form of a pump atomizer.

  Compositions suitable for buccal or sublingual administration include tablets, troches and pastilles, where the active ingredient is formulated with a sugar and a carrier such as gum arabic, tragacanth or gelatin and glycerin.

  A composition for rectal administration is conveniently in the form of a suppository containing a conventional suppository base such as cocoa butter.

  Compositions suitable for transdermal administration include ointments, gels and patches. The composition may be in unit dosage form such as a tablet, capsule or ampoule.

  Each dosage unit for oral administration contains, for example, 1 to 250 mg (for example, 0.1 to 25 mg in the case of parenteral administration) of the compound of formula (I) or a salt thereof calculated as a free base. .

  In addition, the antipsychotic ingredients used in the adjunct therapy of the present invention may be administered in their basic or acidic form as appropriate, or, where appropriate, in the form of a salt or other derivative. All solvates of all the antipsychotics described herein or their salts or derivatives and all other, including but not limited to other crystalline forms, amorphous forms and polymorphs The physical form is within the scope of the present invention. In the case of antipsychotics, their forms and derivatives are those approved for therapeutic administration as monotherapy, including, for example, those mentioned above, but all references to antipsychotics herein are Including salts or other derivatives thereof, as well as all solvates and other physical forms thereof.

  In adjunct therapeutic administration of the present invention, the compound of formula (I) or salt or solvate and the antipsychotic agent or salt, derivative or solvate thereof can each be administered in pure form. Each component is formulated, for example, as a suitable pharmaceutically acceptable and effective composition that provides an effective level of that individual component in the body. The selection of the most suitable pharmaceutical composition for each component is within the skill of the art, and each component may be in the same or different form. Suitable formulations include, but are not limited to, tablets, capsules, powders, granules, troches, suppositories, reconstituted powders, or liquid formulations such as oral or sterile parenteral solutions or suspensions. Can be mentioned.

  For co-administration as a combination composition of a compound of formula (I) and an antipsychotic of the present invention, a compound of formula (I) or a salt or solvate thereof and an antipsychotic and a salt thereof, Derivative or solvate compositions can be administered in pure form, but this combination component, for example, a suitable pharmaceutically acceptable and effective composition that provides an effective level of the individual components in the body As dispensed. The selection of the most suitable pharmaceutical composition for these combination components is within the skill of the art and may be the same or different form for each component. Suitable formulations include, but are not limited to, tablets, sublingual tablets, oral compositions, capsules, powders, granules, troches, suppositories, reconstituted powders, or oral or sterile parenteral solutions or Examples include liquid preparations such as suspensions.

  In order to obtain co-administration consistency, the composition of each of these components, or the combination of these components, is in the form of a unit dose, for example.

  “Treatment” includes prophylaxis if appropriate for the relevant condition.

FLIPR Test Assay A for M ₁ Receptor for Testing Biological Test Agonist / Antagonist Efficacy
Using FLIPR (Fluorometric Imaging Plate Reader) technology, the compounds of the present invention were characterized in a functional assay examining the ability to activate the intracellular calcium pathway in CHO cells stably expressing human muscarinic receptors. Briefly, CHO-M1 cells were seeded (20,000 / well) and grown overnight at 37 ° C. The medium was removed and 30 μL of loading buffer (HBSS with 20 mM HEPES, pH 7.4) containing FLIPR calcium 3 dye (Molecular Devices Co., Sunnyvale, Calif.) Was added according to the manufacturer's instructions. After incubation at 37 ° C. for 45-60 minutes, 10 μL of assay buffer (HBSSd with 20 mM HEPES and 2.5 mM probenecid, pH 7.4) containing the test compound was added to each well on the FLIPR apparatus. The calcium response was monitored to determine the stimulatory effect. The plates were then incubated for an additional 30 minutes before 10 μL of assay buffer containing acetylcholine was added at EC ₈₀ for agonist stimulation. Subsequently, the calcium response was monitored again to determine the antagonism of the compound against acetylcholine. Concentration response curves for both stimulatory and antagonistic effects on the M1 receptor were generated for each compound. The results were imported into ActiveBase data analysis suite (ID Business Slution Inc., Parsippany, NJ), these curves were analyzed by non-linear curve fitting, and the resulting pEC ₅₀ / pIC ₅₀ was calculated. Intrinsic activity of agonist compounds was calculated as a percentage of the maximum FLIPR response elicited by acetylcholine (ie, using EC ₁₀₀ acetylcholine as a control).

Assay B
Using FLIPR (Fluorometric Imaging Plate Reader) technology, the compounds of the present invention were characterized in a functional assay examining the ability to activate the intracellular calcium pathway in CHO cells stably expressing human muscarinic receptors. Briefly, CHO-M1 cells were seeded (15,000 / well) and grown overnight at 37 ° C. The medium was removed and 30 μL loading buffer (2.5 mM probenicid, 2 μM Fluo-4, HBSS containing 500 μM brilliant black, pH 7.4) was added. After incubation at 37 ° C. for 90 minutes, 10 μL of assay buffer (HBSS with 2.5 mM probenecid, pH 7.4) containing the test compound was added to each well on the FLIPR apparatus. The calcium response was monitored to determine the stimulatory effect. The plates were then incubated for an additional 30 minutes before 10 μL of assay buffer containing acetylcholine was added at EC ₈₀ for agonist stimulation. Subsequently, the calcium response was monitored again to determine the antagonism of the compound against acetylcholine. Concentration response curves for both stimulatory and antagonistic effects on the M1 receptor were generated for each compound. The results were imported into ActiveBase data analysis suite (ID Business Solution Inc., Parsippany, NJ), these curves were analyzed by non-linear curve fitting, and the resulting pEC50 / fpKip was calculated. Intrinsic activity of agonist compounds was calculated as a percentage of the maximum FLIPR response elicited by acetylcholine added as a control to the same compound plate and converted to a fraction between 0 and 1 (ie, multiple concentrations as controls) Calculated using the maximum 100% response obtained from fitting an acetylcholine standard curve containing).

The following compound examples were tested in one or both of the above assays and were found to have pEC ₅₀ values> 6.0 and intrinsic activity> 50% at muscarinic M ₁ receptors.

FLIPR test assay A for the M ₁ receptor to examine the intrinsic activity of agonists
To examine the intrinsic activity of M1 agonist compounds, characterization was performed in the FLIPR test in U2OS cells that transiently express human muscarinic M1 receptors. In short, M1 BacMam virus (Ames, RS; Fornwald, JA; Nuthulaganti, P; Trill, JJ; Foley, JJ; Buckley, PT; Kost, TA; Wu, Z and Romanos, MA) (2004) Use Receptors and Channels 10 (3-4): 99-109), 2 × 10e ⁵ / mL cell suspension, 0.1% virus / cell ratio (BacMam recombinant baculoviruses to support G protein-coupled receptor drug discovery. v / v). The virus to cell ratio was determined by functional titration in a separate test to be most appropriate for measuring the intrinsic activity of partial agonists. After mixing with virus suspension, cells were seeded (10,000 / well) and grown overnight at 37 ° C. The next day, the FLIPR test was then performed using the same protocol as described above for CHO-M1 cells. The results were imported into ActiveBase data analysis, these curves were analyzed by non-linear curve fitting and the resulting pEC50 values were calculated. Intrinsic activity of agonist compounds was calculated as a percentage of the maximum FLIPR response elicited by acetylcholine added as a control to the same compound plate and converted to a fraction between 0 and 1 (ie, multiple concentrations as controls) Calculated using the maximum 100% response obtained from fitting an acetylcholine standard curve containing).

Assay B
To examine the intrinsic activity of M1 agonist compounds, CHAR cells were characterized in the FLIPR test in CHO cells that transiently express human muscarinic M1 receptors. In short, M1 BacMam virus (Ames, RS; Fornwald, JA; Nuthulaganti, P; Trill, JJ; Foley, JJ; Buckley, PT; Kost, TA; Wu, Z and Romanos, MA. (2004) Use of BacMam recombinant baculoviruses to support G protein-coupled receptor drug discovery. Receptors and Channels 10 (3-4): 99-109). The virus to cell ratio was determined by functional titration in a separate test to be most appropriate for measuring the intrinsic activity of partial agonists. After mixing with virus suspension, cells were seeded (15,000 / well) and grown overnight at 37 ° C. Alternatively, the cells were then frozen at −140 ° C. in a 1 ml vial at a concentration of 4.8 × 10e7 cells / ml in 90% dialyzed fetal calf serum, 10% dimethyl sulfoxide. The cells were then thawed the day before the assay, seeded (15,000 / well) and grown overnight at 37 ° C.

  The day after seeding, the FLIPR test was performed using the same protocol as described above for CHO-M1 cells. The results were imported into ActiveBase data analysis suite and these curves were analyzed by non-linear curve fitting and the resulting pEC50 values were calculated. Intrinsic activity of agonist compounds was calculated as a percentage of the maximum FLIPR response elicited by acetylcholine added as a control to the same compound plate and converted to a fraction between 0 and 1 (ie multiple concentrations as controls) Calculated using the maximum 100% response obtained from fitting an acetylcholine standard curve containing).

The following compound examples were tested in one or both of the above assays and found to have pEC ₅₀ values> 6.0 and an intrinsic activity of 0.3 or greater at the muscarinic M ₁ receptor.

FLIPR test assay A for M _2-5 receptor to examine receptor subtype selectivity
To examine the selectivity of other muscarinic receptor subtypes of the compounds of the present invention, the compounds were characterized in the FLIPR test in CHO cells stably expressing the human muscarinic receptors M2, M3, M4 or M5. In the case of M2 and M4 receptors, the chimeric G protein Gqi5 was also co-expressed, coupling the receptor to the calcium signaling pathway. Briefly, cells were seeded (20,000 / well) and grown overnight at 37 ° C. The next day, the FLIPR test was then performed using the same protocol as described above for CHO-M1 cells. The results were imported into ActiveBase data analysis, these curves were analyzed by non-linear curve fitting and the resulting pEC50 / pIC50 values were calculated.

Assay B
To examine the selectivity of other muscarinic receptor subtypes of the compounds of the present invention, the compounds were characterized in the FLIPR test in CHO cells stably expressing the human muscarinic receptors M2, M3, M4 or M5. In the case of M2 and M4 receptors, the chimeric G protein Gqi5 was also co-expressed, coupling the receptor to the calcium signaling pathway. Briefly, cells were seeded (15,000 / well) and grown overnight at 37 ° C. The next day, the FLIPR test was then performed using the same protocol as described above for CHO-M1 cells. The results were imported into ActiveBase data analysis, these curves were analyzed by non-linear curve fitting and the resulting pEC50 / fpKi values were calculated.

  The following compound examples were tested in one or both of the above assays and found to be selective for the M1 receptor over the M2, M3, M4 and M5 receptors, with a typical selectivity (pEC50 ratio) of 10 It was over 100 times or more in some cases.

  The invention is further illustrated by the following non-limiting examples. In the following procedures, the described references after each starting material are generally provided by numbers. This is only shown to help skilled chemists. The starting material may not necessarily have been produced from the referenced batch. SCX refers to the sulfonate ion exchange resin supplied by Varian.

  All reactions were performed under argon or can be performed under argon unless otherwise noted (eg, hydrogenation reactions).

（Ｄ１）
１，４−ジオキサスピロ［４．５］デカン−８−オン（６４ｍｍｏｌ、１０ｇ）をエタノール（１２５ｍｌ）に溶解し、０℃にて少量ずつＮａＢＨ_４（１．２当量、７６．８ｍｍｏｌ、２．９ｇ）で処理し、この混合物を室温で１時間攪拌した。反応をＮａＯＨ（２５ｍｌ、２Ｎ水溶液）でクエンチした。この水溶液をジクロロメタンで抽出した（２回）。有機液を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させ、標題化合物８．３ｇ、８２％を無色の油状物として得た。
¹H NMR δ(d⁶DMSO, 400 MHz) 1.44 (4H, m), 1.64 (4H, m), 3.54 (1H, d ブロード), 3.82 (4H, m), 4.48 (1H, d) Description 1.1,4-Dioxaspiro [4.5] decan-8-ol (D1)

(D1)
1,4-Dioxaspiro [4.5] decan-8-one (64 mmol, 10 g) was dissolved in ethanol (125 ml) and NaBH ₄ (1.2 eq, 76.8 mmol, 2.9 g) was added in small portions at 0 ° C. And the mixture was stirred at room temperature for 1 hour. The reaction was quenched with NaOH (25 ml, 2N aqueous solution). This aqueous solution was extracted with dichloromethane (twice). The organics were combined, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated to give 8.3 g, 82% of the title compound as a colorless oil.
¹ H NMR δ (d ⁶ DMSO, 400 MHz) 1.44 (4H, m), 1.64 (4H, m), 3.54 (1H, d broad), 3.82 (4H, m), 4.48 (1H, d)

（Ｄ２）
１，４−ジオキサスピロ［４．５］デカン−８−オール（Ｄ１、５２．５ｍｍｏｌ、８．３ｇ）をジメチルホルムアミド（１００ｍｌ）に溶解し、ＮａＨ（２当量、１０５ｍｍｏｌ、４．２ｇ）を０℃にて少量ずつ加えた。この混合物を０℃で１０分間攪拌し、室温でヨードメタン（２当量、６．５ｍｌ）を加えた。この混合物を室温で２時間攪拌した後、メタノールでクエンチし、酢酸エチルと水とで分液し、２層に分けた。水相を酢酸エチルで抽出し（２回）、合わせた有機液をブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させ、粗化合物を得た。クロマトグラフィー（酢酸エチル／ｎ−ヘキサン）により標題化合物７．３５ｇ、８０％を無色の油状物として得た。
¹H NMR δ(d⁶DMSO, 400 MHz) 1.46 (2H, m),1.56 (2H, m), 1.64 (2H, m), 1.73 (2H, m), 3.21 (3H, s), 3.24 (1H, m), 3.83 (4H, m) Description 2.8- (Methyloxy) -1,4-dioxaspiro [4.5] decane (D2)

(D2)
1,4-Dioxaspiro [4.5] decan-8-ol (D1, 52.5 mmol, 8.3 g) was dissolved in dimethylformamide (100 ml) and NaH (2 eq, 105 mmol, 4.2 g) was dissolved at 0 ° C. Was added in small portions. The mixture was stirred at 0 ° C. for 10 minutes and iodomethane (2 eq, 6.5 ml) was added at room temperature. The mixture was stirred at room temperature for 2 hours, then quenched with methanol, partitioned between ethyl acetate and water and separated into two layers. The aqueous phase was extracted with ethyl acetate (twice) and the combined organics were washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated to give the crude compound. Chromatography (ethyl acetate / n-hexane) afforded 7.35 g, 80% of the title compound as a colorless oil.
¹ H NMR δ (d ⁶ DMSO, 400 MHz) 1.46 (2H, m), 1.56 (2H, m), 1.64 (2H, m), 1.73 (2H, m), 3.21 (3H, s), 3.24 (1H , m), 3.83 (4H, m)

（Ｄ３）
８−（メチルオキシ）−１，４−ジオキサスピロ［４．５］デカン（Ｄ２、６２．２ｍｍｏｌ、１１．９ｇ）を１０ｍｌのテトラヒドロフランに溶解し、ＨＣｌ（５Ｍ水溶液５０ｍ）を室温で加え、この混合物を室温で一晩攪拌した。次に、テトラヒドロフランを蒸発させ、混合物をｐＨ＝１０の塩基性とし、酢酸エチルで抽出し（３回）、有機相を合わせ、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させ、標題化合物８．２ｇを得た（完全に変換）。
¹H NMR δ(d⁶DMSO, 400 MHz) 1.92 (4H, m), 2.20 (2H, m), 2.35 (2H, m), 3.29 (3H, s), 3.53 (1H, m) Description 3.4- (Methyloxy) cyclohexanone (D3)

(D3)
8- (Methyloxy) -1,4-dioxaspiro [4.5] decane (D2, 62.2 mmol, 11.9 g) was dissolved in 10 ml of tetrahydrofuran, HCl (5M aqueous solution 50 m) was added at room temperature, and this mixture was added. Was stirred overnight at room temperature. Tetrahydrofuran is then evaporated and the mixture is basified to pH = 10, extracted with ethyl acetate (3 times), the organic phases are combined, washed with brine, dried over Na ₂ SO ₄ , filtered, solvent Was evaporated to give 8.2 g of the title compound (complete conversion).
¹ H NMR δ (d ⁶ DMSO, 400 MHz) 1.92 (4H, m), 2.20 (2H, m), 2.35 (2H, m), 3.29 (3H, s), 3.53 (1H, m)

（Ｄ４）
４−メトキシシクロヘキサノン（Ｄ３、４．５ｇ、４０ｍｍｏｌ）、ジクロロメタン（２００ｍｌ）、４−ピペリジニルカルバミン酸１，１−ジメチルエチル（９．０ｇ；４５ｍｍｏｌ）およびトリアセトキシ水素化ホウ素ナトリウム（１６．０ｇ、８０ｍｍｏｌ）の混合物を室温で１８時間攪拌した後、ｐＨ９にてジクロロメタンと水とで分液した。乾燥させ、蒸発させ、クロマトグラフィー（５０ｇシリカ、ジクロロメタン＋ＮＨ_３中０〜１０％のメタノール）により標題化合物をシスおよびトランス異性体の混合物７．０ｇとして得た。 Description 4. [1- (4-Methoxycyclohexyl) -4-piperidinyl] carbamic acid cis / trans-1,1-dimethylethyl (D4)

(D4)
4-methoxycyclohexanone (D3, 4.5 g, 40 mmol), dichloromethane (200 ml), 1,1-dimethylethyl 4-piperidinylcarbamate (9.0 g; 45 mmol) and sodium triacetoxyborohydride (16.0 g) , 80 mmol) was stirred at room temperature for 18 hours and then partitioned between dichloromethane and water at pH 9. Drying, evaporation and chromatography (50 g silica, dichloromethane + 0-10% methanol in NH ₃ ) afforded the title compound as a mixture of cis and trans isomers, 7.0 g.

（Ｄ５）
［１−（４−メトキシシクロヘキシル）−４−ピペリジニル］カルバミン酸シス／トランス１，１−ジメチルエチル（Ｄ４、７．０ｇ；２２ｍｍｏｌ）、ジクロロメタン（５０ｍｌ）およびジオキサン中４ＭのＨＣｌ（２５ｍｌ；１００ｍｍｏｌ）の混合物を室温で４時間維持した。蒸発させて標題化合物６．３ｇを得た。 Description 5. Cis / trans-1- (4-methoxycyclohexyl) -4-piperidineamine dihydrochloride (D5)

(D5)
[1- (4-Methoxycyclohexyl) -4-piperidinyl] carbamic acid cis / trans 1,1-dimethylethyl (D4, 7.0 g; 22 mmol), dichloromethane (50 ml) and 4M HCl in dioxane (25 ml; 100 mmol) Was maintained at room temperature for 4 hours. Evaporation gave 6.3 g of the title compound.

（Ｄ６ａ） （Ｄ６ｂ）
アルゴン下、室温で、ジメチルホルムアミド（２５ｍｌ）中、３−フルオロ−４−ニトロトルエン（０．８７ｇ）の攪拌溶液をジイソプロピルエチルアミン（２．９ｍｌ）および１−［４−（メトキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ５、シス：トランス混合物、１．２ｇ）で処理し、週末にかけて５５℃で加熱した。冷却反応物を酢酸エチルで希釈し、水で３回、さらにブラインで１回洗浄した後、乾燥させ、蒸発させ、クロマトグラフィーに付し（０〜２５％酢酸エチル／ヘキサンで溶出するＢｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカカラム）、標題化合物のシス（Ｄ６ａ、３００ｍｇ）およびトランス（Ｄ６ｂ、１００ｍｇ）異性体を得た。 Description 6. Cis and trans-N- (5-methyl-2-nitrophenyl) -1- (4-methoxycyclohexyl) -4-piperidinamine (D6a, D6b)

(D6a) (D6b)
A stirred solution of 3-fluoro-4-nitrotoluene (0.87 g) in dimethylformamide (25 ml) at room temperature under argon was added diisopropylethylamine (2.9 ml) and 1- [4- (methoxy) cyclohexyl] -4- Treated with piperidineamine dihydrochloride (D5, cis: trans mixture, 1.2 g) and heated at 55 ° C. over the weekend. The cooled reaction was diluted with ethyl acetate and washed three times with water and once with brine, then dried, evaporated and chromatographed (Biotage KP- eluting with 0-25% ethyl acetate / hexanes). NH (TM) -silica column), cis (D6a, 300 mg) and trans (D6b, 100 mg) isomers of the title compound were obtained.

（Ｄ７）
５０℃にて、ＥｔＯＨ（２０ｍｌ）中、シスＮ−（５−メチル−２−ニトロフェニル）−１−（４−メトキシシクロヘキシル）−４−ピペリジンアミン（Ｄ６ａ、３００ｍｇ；０．９ｍｍｏｌ）の攪拌懸濁液をラネーニッケル（５０％水性懸濁液１．８ｍｌ）で処理した後、ヒドラジン水和物（０．４５ｍｌ）を滴下した。この混合物を同じ温度で１時間加熱した後、セライトで濾過し、濾液を蒸発させ、まずトルエン、次いでジエチルエーテルから再蒸発させ、標題化合物３２０ｍｇを得た。 Description 7. Cis-5-methyl-N- [1- (4-methoxycyclohexyl) -4-piperidinyl] -1,2-benzenediamine (D7)

(D7)
Stirring of cis N- (5-methyl-2-nitrophenyl) -1- (4-methoxycyclohexyl) -4-piperidineamine (D6a, 300 mg; 0.9 mmol) in EtOH (20 ml) at 50 ° C. The suspension was treated with Raney nickel (1.8 ml of 50% aqueous suspension), and hydrazine hydrate (0.45 ml) was added dropwise. The mixture was heated at the same temperature for 1 hour, then filtered through celite, the filtrate evaporated and re-evaporated first from toluene and then diethyl ether to give 320 mg of the title compound.

（Ｄ８）
５０℃にて、エタノール（６ｍｌ）中、トランスＮ−（３−フルオロ−５−メチル−２−ニトロフェニル）−１−（４−メトキシシクロヘキシル）−４−ピペリジンアミン（Ｄ６ｂ、１００ｍｇ、０．３ｍｍｏｌ）の攪拌懸濁液をラネーニッケル（１０％水性懸濁液０．６ｍｌ）で処理した後、ヒドラジン水和物（０．１５ｍｌ、１０当量）を滴下した。この混合物を同じ温度で１時間加熱した後、Ｋｉｅｓｅｌｇｕｈｒで濾過し、濾液を蒸発させ、トルエン、次いでＥｔ_２Ｏから再蒸発させ、標題化合物１００ｍｇを得た。 Description 8. Trans-5-methyl-N- [1- (4-methoxycyclohexyl) -4-piperidinyl] -1,2-benzenediamine (D8)

(D8)
Trans N- (3-fluoro-5-methyl-2-nitrophenyl) -1- (4-methoxycyclohexyl) -4-piperidinamine (D6b, 100 mg, 0.3 mmol in ethanol (6 ml) at 50 ° C. ) Was treated with Raney nickel (0.6 ml of 10% aqueous suspension), and hydrazine hydrate (0.15 ml, 10 equivalents) was added dropwise. The mixture was heated at the same temperature for 1 hour then filtered through Kieselguhr and the filtrate was evaporated and re-evaporated from toluene and then Et ₂ O to give 100 mg of the title compound.

（Ｄ９）
１０℃にてアルゴン下、Ｎ−メチルピロリジノン（３５ｍｌ）中、１，４−ジオキサスピロ［４．５］デカン−８−オール（Ｄ１、４．０ｇ、０．０２５ｍｏｌ）の攪拌溶液をＮａＨ（６０％油分散物１．１ｇ、０．０２８ｍｏｌ）で少量ずつ処理し、１時間維持した後、ヨードエタン（２．６ｍｌ、０．０３２ｍｏｌ）を加えた。この混合物を室温まで温め、１８時間攪拌した。さらに、ＮａＨ（６０％油分散物０．５ｇ；０．０１２ｍｏｌ）を加え、この混合物を０．５時間攪拌した後、さらなるヨードエタン（２．０ｍｌ；０．０２５ｍｏｌ）を加え、この混合物を室温で３時間維持した。この混合物をエタノール（１ｍｌ）で注意深く処理して過剰なＮａＨを破壊した後、水（３００ｍｌ）を加え、この混合物をヘキサン（２×２００ｍｌ）で抽出した。合わせた抽出液を水（２×２００ｍｌ）で洗浄した後、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、鉱油残渣が混入した標題化合物を含有する無色の油状物（４．７ｇ）を得た。
¹HNMR δ(CDCl₃, 400 MHz): 1.20 (3H, t), 1.50-1.60 (2H, m), 1.63-1.77 (2H, m), 1.77-1.90 (4H, m), 3.35-3.43 (1H, m), 3.49 (2H, q), 3.90-4.00 (4H, m) Description 9.8- (Ethyloxy) -1,4-dioxaspiro [4.5] decane (D9)

(D9)
A stirred solution of 1,4-dioxaspiro [4.5] decan-8-ol (D1, 4.0 g, 0.025 mol) in N-methylpyrrolidinone (35 ml) at 10 ° C. under argon was added NaH (60% Oil dispersion 1.1 g, 0.028 mol) was treated in small portions and maintained for 1 hour, after which iodoethane (2.6 ml, 0.032 mol) was added. The mixture was warmed to room temperature and stirred for 18 hours. Further NaH (60% oil dispersion 0.5 g; 0.012 mol) was added and the mixture was stirred for 0.5 h before additional iodoethane (2.0 ml; 0.025 mol) was added and the mixture was allowed to cool at room temperature. Maintained for 3 hours. The mixture was carefully treated with ethanol (1 ml) to destroy excess NaH, then water (300 ml) was added and the mixture was extracted with hexane (2 × 200 ml). The combined extracts were washed with water (2 × 200 ml), then dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a colorless oil (4.7 g) containing the title compound contaminated with mineral oil residue. It was.
¹ HNMR δ (CDCl ₃ , 400 MHz): 1.20 (3H, t), 1.50-1.60 (2H, m), 1.63-1.77 (2H, m), 1.77-1.90 (4H, m), 3.35-3.43 (1H , m), 3.49 (2H, q), 3.90-4.00 (4H, m)

（Ｄ１０）
室温にてアルゴン下、テトラヒドロフラン（１０ｍｌ）中、８−（エチルオキシ）−１，４−ジオキサスピロ［４．５］デカン（Ｄ９、４．７ｇ、０．０２５ｍｏｌ）の溶液を５Ｍ ＨＣｌ（４０ｍｌ）で処理し、１８時間攪拌し、この段階で濃ＨＣｌ（５ｍｌ）を加え、この混合物を４０℃で３．５時間攪拌し、反応を完了させた。得られた混合物を水（７５ｍｌ）で希釈し、ジクロロメタン（２×８０ｍｌ）で抽出した。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、２０℃を超えない部分真空下で注意深く濃縮し、標題化合物を淡黄色の油状物として得た（３．８ｇ、純度〜９０％）。
¹H NMR δ(CDCl₃, 400 MHz): 1.25 (3H, t), 1.90-2.00 (2H, m), 2.01-2.13 (2H, m), 2.20-2.32 (2H, m), 2.53-2.65 (2H, m), 3.55 (2H, q), 3.58-3.70 (1H, m) Description 10.4- (Ethyloxy) cyclohexanone (D10)

(D10)
Treat a solution of 8- (ethyloxy) -1,4-dioxaspiro [4.5] decane (D9, 4.7 g, 0.025 mol) with 5M HCl (40 ml) in tetrahydrofuran (10 ml) at room temperature under argon. And stirred for 18 hours, at which point concentrated HCl (5 ml) was added and the mixture was stirred at 40 ° C. for 3.5 hours to complete the reaction. The resulting mixture was diluted with water (75 ml) and extracted with dichloromethane (2 × 80 ml). The combined extracts were dried (Na ₂ SO ₄ ) and carefully concentrated under partial vacuum not exceeding 20 ° C. to give the title compound as a pale yellow oil (3.8 g, purity ˜90%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.25 (3H, t), 1.90-2.00 (2H, m), 2.01-2.13 (2H, m), 2.20-2.32 (2H, m), 2.53-2.65 ( 2H, m), 3.55 (2H, q), 3.58-3.70 (1H, m)

Ｄ１１ａ Ｄ１１ｂ
室温にてアルゴン下、ジクロロメタン（１００ｍｌ）中、４−（エチルオキシ）シクロヘキサノン（Ｄ１０、３．５ｇ、≦０．０２５ｍｏｌ）の攪拌溶液を４−ピペリジニルカルバミン酸１，１−ジメチルエチル（５．０ｇ、０．０２５ｍｏｌ）で処理した後、トリアセトキシ水素化ホウ素ナトリウム（７．４ｇ、０．０３５ｍｏｌ）を５分かけて少量ずつ加え、その後、得られた混合物を室温で２０時間よく攪拌した。反応混合物をメタノール（８ｍｌ）で処理し、得られた溶液を室温で３日間放置した後、５％Ｎａ_２ＣＯ_３溶液（１００ｍｌ）を加え、この混合物をジクロロメタン（２００ｍｌ）で抽出した。抽出液をブラインで洗浄した後、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残った黄色油状物を６０〜８０石油エーテル（１００ｍｌ）に溶解し、室温で一晩放置したところで、生じた結晶を濾別し、石油で洗浄し、乾燥させ、１．７ｇの標題化合物トランス異性体と出発４−ピペリジニルカルバミン酸１，１−ジメチルエチルの〜４５：５５混合物を得た。０〜５％メタノール／ジクロロメタンで溶出するシリカゲルでのカラムクロマトグラフィーにより精製し、純粋な標題化合物トランス異性体（Ｄ１１ｂ）を白色固体として得た（９３０ｍｇ）。
¹H NMR δ(CDCl₃, 400 MHz): 1.15-1.50 (6H, m), 1.18 (3H, t), 1.44 (9H, s), 1.82-2.00 (4H, m), 2.04-2.14 (2H, m), 2.20-2.32 (3H, m), 2.85 (2H, br d), 3.10-3.20 (1H, m), 3.38-3.50 (1H, m), 3.50 (2H, q), 4.40 (1H, br d) Description 11. {1- [cis-4- (ethyloxy) cyclohexyl] -4-piperidinyl} carbamic acid 1,1-dimethylethyl (D11a) and {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} carbamic acid 1,1-dimethylethyl (D11b)

D11a D11b
A stirred solution of 4- (ethyloxy) cyclohexanone (D10, 3.5 g, ≦ 0.025 mol) in dichloromethane (100 ml) under argon at room temperature was 1,1-dimethylethyl 4-piperidinylcarbamate (5. After treatment with 0 g, 0.025 mol), sodium triacetoxyborohydride (7.4 g, 0.035 mol) was added in portions over 5 minutes, and then the resulting mixture was stirred well at room temperature for 20 hours. The reaction mixture was treated with methanol (8 ml) and the resulting solution was allowed to stand at room temperature for 3 days before 5% Na ₂ CO ₃ solution (100 ml) was added and the mixture was extracted with dichloromethane (200 ml). The extract was washed with brine, then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The remaining yellow oil was dissolved in 60-80 petroleum ether (100 ml) and allowed to stand overnight at room temperature, whereupon the resulting crystals were filtered off, washed with petroleum, dried and 1.7 g of the title compound trans isomerized. To give a ˜45: 55 mixture of 1,1-dimethylethyl 4-piperidinylcarbamate. Purification by column chromatography on silica gel eluting with 0-5% methanol / dichloromethane gave the pure title compound trans isomer (D11b) as a white solid (930 mg).
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.15-1.50 (6H, m), 1.18 (3H, t), 1.44 (9H, s), 1.82-2.00 (4H, m), 2.04-2.14 (2H, m), 2.20-2.32 (3H, m), 2.85 (2H, br d), 3.10-3.20 (1H, m), 3.38-3.50 (1H, m), 3.50 (2H, q), 4.40 (1H, br d)

  The crystallization mother liquor was concentrated in vacuo to give 6 g of a yellow oil containing the title compound cis isomer (D11a) as a ˜4: 1 mixture with the trans isomer.

（Ｄ１２）
方法Ａ
｛１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝カルバミン酸１，１−ジメチルエチル（Ｄ１１ｂ、９２０ｍｇ、４．２９９ｍｍｏｌ）をジクロロメタン（６ｍｌ）に溶解し、室温にてＨＣｌ（１，４−ジオキサン中４Ｍ溶液２１ｍｌ）で処理した。この混合物を室温で１時間攪拌し、溶媒を蒸発させた。粗物質をＳＣＸカートリッジに通し、三塩基標題化合物を淡褐色粉末として得た（８６５ｍｇ、４．０ｍｍｏｌ、８９％）。Ｍ^＋＋Ｈ＝２２７ Description 12.1- (trans-4-ethoxycyclohexyl) piperidin-4-amine (D12)

(D12)
Method A
{1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} carbamic acid 1,1-dimethylethyl (D11b, 920 mg, 4.299 mmol) was dissolved in dichloromethane (6 ml) and HCl (1 , 4-dioxane in a 4M solution (21 ml). The mixture was stirred at room temperature for 1 hour and the solvent was evaporated. The crude material was passed through an SCX cartridge to give the tribasic title compound as a light brown powder (865 mg, 4.0 mmol, 89%). M ⁺ + H = 227

Method B
A mixture of trans-1- (4-ethoxycyclohexyl) -4-piperidone (D45, 13.2 g), 2M ammonia in methanol (300 ml) and 10% palladium on carbon paste (4 g) was charged with hydrogen at 50 psi overnight at room temperature. After addition, additional 10% palladium on carbon paste (1 g) was added and hydrogenated at 50 psi over the weekend, then filtered and evaporated to give the title compound (9.5 g) as an oil.

（Ｄ１３）
乾燥ジメチルホルムアミド（６ｍｌ）中、１−（トランス−４−エトキシシクロヘキシル）ピペリジン−４−アミン（Ｄ１２、１５０ｍｇ、０．７０ｍｍｏｌ）の溶液に、室温にてジイソプロピルエチルアミン（０．１１ｍｌ、１当量、０．７０ｍｍｏｌ）および３−フルオロ−４−ニトロトルエン（１０３ｍｇ、１当量、０．７０ｍｍｏｌ）を加え、この混合物を８０℃で２４時間還流させた。ＴＬＣでは反応が完了していないことが示された。次に、１５０℃にて計３０分間マイクロ波により反応を完了させた。その後、この粗混合物を室温まで冷却し、粗物質を水に注ぎ、この水溶液を酢酸エチルで抽出し（２回）、有機液をブラインと水で交互に洗浄した（２回）。有機液を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させて粗生成物を得、これをＢｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカカラムでのクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）により精製し、標題化合物を黄色ガムとして得た（１１８ ｍｇ、５０％）。Ｍ^＋＋Ｈ＝３６２ 13.1- [Trans-4- (ethyloxy) cyclohexyl] -N- (5-methyl-2-nitrophenyl) -4-piperidineamine (D13)

(D13)
To a solution of 1- (trans-4-ethoxycyclohexyl) piperidin-4-amine (D12, 150 mg, 0.70 mmol) in dry dimethylformamide (6 ml) at room temperature is diisopropylethylamine (0.11 ml, 1 equivalent, 0 .70 mmol) and 3-fluoro-4-nitrotoluene (103 mg, 1 eq, 0.70 mmol) were added and the mixture was refluxed at 80 ° C. for 24 h. TLC showed that the reaction was not complete. The reaction was then completed by microwave at 150 ° C. for a total of 30 minutes. The crude mixture was then cooled to room temperature, the crude material was poured into water, the aqueous solution was extracted with ethyl acetate (twice), and the organic was washed alternately with brine and water (twice). The organics were combined, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated to give the crude product which was chromatographed on a Biotage KP-NH ™ -silica column (ethyl acetate / n-hexane). ) To give the title compound as a yellow gum (118 mg, 50%). M ⁺ + H = 362

（Ｄ１４）
１−［トランス−４−（エチルオキシ）シクロヘキシル］−Ｎ−（５−メチル−２−ニトロフェニル）−４−ピペリジンアミン（Ｄ１３、１１８ｍｇ、０．３３ｍｍｏｌ）をエタノール（３ｍｌ）に溶解し、室温にて、ラネーニッケルの水性懸濁液（５０％懸濁液１ｍｌ）を加えた。この混合物を室温で３０分間攪拌した後、ヒドラジン一水和物（０．１５ｍｌ、１５当量、５．０ｍｍｏｌ）を３０分かけて加えた。一晩放置して反応させた。反応混合物をセライトで濾過し、溶媒を蒸発させ、標題化合物を褐色固体として得た（１１０ｍｇ、１００％）。Ｍ^＋＋Ｈ＝３３２ Description 14. (2-Amino-5-methylphenyl) {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} amine (D14)

(D14)
1- [trans-4- (ethyloxy) cyclohexyl] -N- (5-methyl-2-nitrophenyl) -4-piperidinamine (D13, 118 mg, 0.33 mmol) was dissolved in ethanol (3 ml) and brought to room temperature. An aqueous suspension of Raney nickel (1 ml of 50% suspension) was added. After the mixture was stirred at room temperature for 30 minutes, hydrazine monohydrate (0.15 ml, 15 equivalents, 5.0 mmol) was added over 30 minutes. The reaction was allowed to stand overnight. The reaction mixture was filtered through celite and the solvent was evaporated to give the title compound as a brown solid (110 mg, 100%). M ⁺ + H = 332

（Ｄ１５）
｛１−［４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝カルバミン酸シス／トランス−１，１−ジメチルエチル（Ｄ１１ａ、２．６ｇ、８．０ｍｍｏｌ）をジクロロメタン（１２ｍｌ）に溶解し、ＨＣｌ（１，４−ジオキサン中４Ｍ溶液３５ｍｌ）で処理した。この混合物を室温で１時間攪拌し、溶媒を蒸発させ、標題化合物をシス／トランス異性体の混合物として得た（２．１７ｇ、９．６３１ｍｍｏｌ、１００％）。Ｍ^＋＋Ｈ＝２２７ Description 15. Cis / trans-1- (4-ethoxycyclohexyl) piperidin-4-amine dihydrochloride (D15)

(D15)
{1- [4- (Ethyloxy) cyclohexyl] -4-piperidinyl} carbamic acid cis / trans-1,1-dimethylethyl (D11a, 2.6 g, 8.0 mmol) was dissolved in dichloromethane (12 ml) and HCl ( Treated with 35 ml of a 4M solution in 1,4-dioxane). The mixture was stirred at room temperature for 1 hour and the solvent was evaporated to give the title compound as a mixture of cis / trans isomers (2.17 g, 9.631 mmol, 100%). M ⁺ + H = 227

（Ｄ１６）
室温にて、２−フルオロ−４−メチル−１−ニトロベンゼン（３００ｍｇ、１当量）、シス／トランス１−［４−（エチルオキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ１５、６００ｍｇ、１当量、２ｍｍｏｌ）およびジイソプロピルエチルアミン（１ｍｌ、３当量）をジメチルホルムアミド（２．５ｍｌ）に部分溶解し、この混合物をマイクロ波により２００℃で２５分間加熱した。次に、この粗混合物を室温まで冷却し、水／ブラインに注ぎ、この水溶液を酢酸エチルで抽出し（２回）、有機液をブラインと水で交互に洗浄した（２回）。有機液を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させて粗生成物を得、これをＢｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカカラムでのクロマトグラフィーにより精製し、標題化合物（シス異性体）（１６０ｍｇ）を得た。Ｍ^＋＋Ｈ＝３６２ Description 16.1- [cis-4- (Ethyloxy) cyclohexyl] -N- (5-methyl-2-nitrophenyl) -4-piperidinamine (D16)

(D16)
At room temperature, 2-fluoro-4-methyl-1-nitrobenzene (300 mg, 1 equivalent), cis / trans 1- [4- (ethyloxy) cyclohexyl] -4-piperidineamine dihydrochloride (D15, 600 mg, 1 equivalent) 2 mmol) and diisopropylethylamine (1 ml, 3 eq) were partially dissolved in dimethylformamide (2.5 ml) and the mixture was heated by microwave at 200 ° C. for 25 minutes. The crude mixture was then cooled to room temperature, poured into water / brine, the aqueous solution was extracted with ethyl acetate (twice), and the organic was washed with brine and water alternately (twice). The organics were combined, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated to give the crude product which was purified by chromatography on a Biotage KP-NH ™ -silica column to give the title compound ( Cis isomer) (160 mg) was obtained. M ⁺ + H = 362

（Ｄ１７）
１−［シス−４−（エチルオキシ）シクロヘキシル］−Ｎ−（５−メチル−２−ニトロフェニル）−４−ピペリジンアミン（Ｄ１６、１６０ｍｇ、０．４４ｍｍｏｌ）をエタノール（３ｍｌ）に溶解し、室温にて、ラネーニッケルの水性懸濁液（５０％懸濁液１ｍｌ）を加えた。この混合物を３０分間攪拌した後、ヒドラジン一水和物（０．２１ｍｌ、１５当量、６．６ｍｍｏｌ）を３０分かけて加えた。一晩放置して反応させた。反応混合物をセライトで濾過し、溶媒を蒸発させ、標題化合物を褐色固体として得た（１４７ｍｇ、１００％）。Ｍ^＋＋Ｈ＝３３２ Description 17. (2-Amino-5-methylphenyl) {1- [cis-4- (ethyloxy) cyclohexyl] -4-piperidinyl} amine (D17)

(D17)
1- [cis-4- (Ethyloxy) cyclohexyl] -N- (5-methyl-2-nitrophenyl) -4-piperidinamine (D16, 160 mg, 0.44 mmol) was dissolved in ethanol (3 ml) and brought to room temperature. An aqueous suspension of Raney nickel (1 ml of 50% suspension) was added. After stirring the mixture for 30 minutes, hydrazine monohydrate (0.21 ml, 15 eq, 6.6 mmol) was added over 30 minutes. The reaction was allowed to stand overnight. The reaction mixture was filtered through celite and the solvent was evaporated to give the title compound as a brown solid (147 mg, 100%). M ⁺ + H = 332

（Ｄ１８）
０℃にてアルゴン下、Ｎ−メチルピロリジン−２−オン（３５ｍｌ）中、１，４−ジオキサスピロ［４．５］デカン−８−オール（Ｄ１、４ｇ、２５．３ｍｍｏｌ）および１−ブロモプロパン（２．７８ｍｌ、３０．３６ｍｍｏｌ）の攪拌溶液をＮａＨ（６０％、１．１ｇ）で処理した後、室温まで温め、３時間攪拌した。１−ブロモプロパン（１ｍｌ、１０．９２ｍｍｏｌ）を加え、この反応物を一晩攪拌した。水を加え、この混合物をヘキサンで抽出した（２０ｍｌ×３）。これらの有機画分を回収し、ＭｇＳＯ４で乾燥させた後、濃縮し、標題化合物を無色の液体として得た（３．４ｇ、収率６８％）。
1H NMR δ(CDCl3 400MHz): 0.8-0.9 (3H, t), 1.5-1.85 (10H, m), 3.4 (3H, m), 3.9 (4H, m) Description 18.8- (propyloxy) -1,4-dioxaspiro [4.5] decane (D18)

(D18)
1,4-Dioxaspiro [4.5] decan-8-ol (D1, 4 g, 25.3 mmol) and 1-bromopropane (N 1) in N-methylpyrrolidin-2-one (35 ml) at 0 ° C. under argon. A stirred solution of 2.78 ml, 30.36 mmol) was treated with NaH (60%, 1.1 g), then warmed to room temperature and stirred for 3 hours. 1-Bromopropane (1 ml, 10.92 mmol) was added and the reaction was stirred overnight. Water was added and the mixture was extracted with hexane (20 ml × 3). These organic fractions were collected, dried over MgSO 4 and concentrated to give the title compound as a colorless liquid (3.4 g, 68% yield).
1H NMR δ (CDCl3 400MHz): 0.8-0.9 (3H, t), 1.5-1.85 (10H, m), 3.4 (3H, m), 3.9 (4H, m)

（Ｄ１９）
テトラヒドロフラン（３５ｍｌ）中、８−（プロピルオキシ）−１，４−ジオキサスピロ［４．５］デカン（Ｄ１８、３．４ｇ、１７ｍｍｏｌ）の攪拌溶液を５Ｍ ＨＣｌ（３５ｍｌ）で処理し、アルゴン下、室温で一晩、攪拌した。テトラヒドロフランを真空下で部分的に除去し、水（〜２０ｍｌ）を加え、この溶液をジクロロメタンで抽出し（〜２０ｍｌ×３）、抽出液をＭｇＳＯ_４で乾燥させた後、真空濃縮し、標題化合物を淡黄色の油状物として得た（２．７ｇ、収率９８％）。この粗物質をそれ以上精製せずに次の工程で用いた。 Description 19.4- (propyloxy) cyclohexanone (D19)

(D19)
A stirred solution of 8- (propyloxy) -1,4-dioxaspiro [4.5] decane (D18, 3.4 g, 17 mmol) in tetrahydrofuran (35 ml) was treated with 5M HCl (35 ml) and at room temperature under argon. Stir overnight. Tetrahydrofuran was partially removed under vacuum, water (˜20 ml) was added, the solution was extracted with dichloromethane (˜20 ml × 3), the extract was dried over MgSO ₄ and then concentrated in vacuo. Was obtained as a pale yellow oil (2.7 g, 98% yield). This crude material was used in the next step without further purification.

（Ｄ２０）
室温にてアルゴン下、ジクロロメタン（３０ｍｌ）中、４−プロポキシシクロヘキサノン（Ｄ１９、２．７ｇ、０．０１７ｍｏｌ）および４−ピペリジニルカルバミン酸１，１−ジメチルエチル（３．６ｇ、０．０１７ｍｏｌ）の攪拌溶液をトリアセトキシ水素化ホウ素ナトリウム（３．８ｇ、０．０２ｍｏｌ）で処理した後、得られた混合物を室温で一晩よく攪拌した。この混合物を水で処理し、ジクロロメタンで抽出し（３０ｍｌ×３）、有機液を回収し、ＭｇＳＯ_４で乾燥させた後、真空濃縮した。粗物質をＳＣＸカートリッジにて、まず、ジクロロメタンで溶出して不純物を除去した後、メタノール中２ＭのＮＨ_３で溶出して、少量の出発材料を含む異性体混合物を回収した。この混合物をシリカカラムでクロマトグラフィーに付し（粗物質３．４ｇに対して１００ｇ：メタノール／ジクロロメタン中０．４ＭのＮＨ_３ ５％〜５％３ＣＶ、５％〜２０％１０ＣＶ、２０％〜２０％２ＣＶ）、２．１ｇの標題化合物混合物を得た（収率３６％）。 Description 20. {1- [4- (propyloxy) cyclohexyl] -4-piperidinyl} carbamic acid cis / trans-1,1-dimethylethyl (D20)

(D20)
4-propoxycyclohexanone (D19, 2.7 g, 0.017 mol) and 1,1-dimethylethyl 4-piperidinylcarbamate (3.6 g, 0.017 mol) in dichloromethane (30 ml) at room temperature under argon. Was treated with sodium triacetoxyborohydride (3.8 g, 0.02 mol) and the resulting mixture was stirred well at room temperature overnight. The mixture was treated with water and extracted with dichloromethane (30 ml × 3), the organics were collected, dried over MgSO ₄ and concentrated in vacuo. The crude material was eluted on a SCX cartridge, first with dichloromethane to remove impurities, then with 2M NH ₃ in methanol to recover an isomer mixture containing a small amount of starting material. The mixture was chromatographed on a silica column (100 g against 3.4 g crude material: 0.4 M NH ₃ in methanol / dichloromethane 5% -5% 3 CV, 5% -20% 10 CV, 20% -20 % 2CV), 2.1 g of the title compound mixture was obtained (yield 36%).

（Ｄ２１）
アルゴン下、室温にて、ジエチルエーテル（１５ｍｌ）中、｛１−［４−（プロピルオキシ）シクロヘキシル］−４−ピペリジニル｝カルバミン酸シス／トランス−１，１−ジメチルエチル（Ｄ２０、２．１ｇ；６．１７ｍｍｏｌ）の混合物を、ジエチルエーテル（１５ｍｌ）中１ＭのＨＣｌ溶液で処理し、一晩攪拌した。白色沈殿を含むこの混合物を濾取した後、乾燥させ、標題混合物を白色固体として得た（１．２ｇ、収率８１％）。 Description 21. Cis / trans-1- [4- (propyloxy) cyclohexyl] -4-piperidineamine dihydrochloride (D21)

(D21)
{1- [4- (propyloxy) cyclohexyl] -4-piperidinyl} carbamate cis / trans-1,1-dimethylethyl (D20, 2.1 g; in diethyl ether (15 ml) at room temperature under argon; 6.17 mmol) was treated with a 1M HCl solution in diethyl ether (15 ml) and stirred overnight. The mixture containing a white precipitate was collected by filtration and dried to give the title mixture as a white solid (1.2 g, 81% yield).

（Ｄ２２ａ） （Ｄ２２ｂ）
ジメチルホルムアミド（２０ｍｌ）中、シス／トランス−１−［４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ２１、１．２ｇ、３．８ｍｍｏｌ）、３−フルオロ−４−ニトロトルエン（５７０ｍｇ、３．８ｍｍｏｌ）およびジイソプロピルエチルアミン（２．５ｍｌ １４．７ｍｍｏｌ；３当量）の混合物をアルゴン下、８０℃で一晩、攪拌および加熱した。この混合物を水で洗浄し、ジクロロメタンで抽出した。有機層をＳＣＸカートリッジで溶出し、メタノール中２ＭのＮＨ_３で溶出することによりシス／トランス混合物を回収した。異性体の分離はＢｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカカラムでのクロマトグラフィー（粗物質１．４ｇに対して１００ｇ：０％〜２０％酢酸エチル／ヘキサン、２０ＣＶ）により得られた。このクロマトグラフィーを２回繰り返し、４１０ｍｇのシス異性体と３４０ｍｇのトランス異性体を得た（５５％収率）。
シス(D22a): ¹H NMR δ(CDCl₃ 400MHz): 0.9 (3H, t), 1.2-1.35 (4H, m), 1.55-17 (4H, m), 1.9 (2H, m), 2.1 (4H, m), 2.35 (3H, s), 2.35 (1H, m), 2.4 (2H, m), 2.9 (2H, m), 3.1-3.2 (1H, m), 3.4 (2H, t), 3.55 (1H, m), 6.4 (1H, d), 6.6 (1H, s), 8.05 (1H, d), 8.2 (1H, d)
MH⁺ 376および377
トランス(D22b): ¹H NMR δ(CDCl₃ 400MHz): 0.9 (3H, t), 1.4 (2H, m), 1.55-175 (8H, m), 2.0 (2H, m), 2.1 (2H, m), 2.3 (3H, s), 2.4 (1H, m), 2.5 (2H, m), 2.9 (2H, m), 3.35 (2H, t), 3.5 (1H, m), 3.55 (1H, m), 6.4 (1H, d), 6.6 (1H, s), 8.05 (1H, d), 8.2 (1H, d)
MH⁺ 376および377 Description 22. N- (5-methyl-2-nitrophenyl) -1- [cis-4- (propyloxy) cyclohexyl] -4-piperidinamine (D22a) and N- (5-methyl-2-nitrophenyl) -1- [Trans-4- (propyloxy) cyclohexyl] -4-piperidineamine (D22b)

(D22a) (D22b)
Cis / trans-1- [4- (propyloxy) cyclohexyl] -4-piperidineamine dihydrochloride (D21, 1.2 g, 3.8 mmol), 3-fluoro-4-nitrotoluene (20 ml) in dimethylformamide (20 ml) A mixture of 570 mg, 3.8 mmol) and diisopropylethylamine (2.5 ml 14.7 mmol; 3 eq) was stirred and heated at 80 ° C. under argon overnight. The mixture was washed with water and extracted with dichloromethane. The organic layer was eluted with an SCX cartridge and the cis / trans mixture was recovered by eluting with 2M NH ₃ in methanol. Isomeric separation was obtained by chromatography on a Biotage KP-NH ™ -silica column (100 g: 0% -20% ethyl acetate / hexane, 20 CV for 1.4 g of crude material). This chromatography was repeated twice to give 410 mg cis isomer and 340 mg trans isomer (55% yield).
Cis (D22a): ¹ H NMR δ (CDCl ₃ 400 MHz): 0.9 (3H, t), 1.2-1.35 (4H, m), 1.55-17 (4H, m), 1.9 (2H, m), 2.1 (4H , m), 2.35 (3H, s), 2.35 (1H, m), 2.4 (2H, m), 2.9 (2H, m), 3.1-3.2 (1H, m), 3.4 (2H, t), 3.55 ( 1H, m), 6.4 (1H, d), 6.6 (1H, s), 8.05 (1H, d), 8.2 (1H, d)
MH ⁺ 376 and 377
Transformer (D22b): ¹ H NMR δ (CDCl ₃ 400 MHz): 0.9 (3H, t), 1.4 (2H, m), 1.55-175 (8H, m), 2.0 (2H, m), 2.1 (2H, m ), 2.3 (3H, s), 2.4 (1H, m), 2.5 (2H, m), 2.9 (2H, m), 3.35 (2H, t), 3.5 (1H, m), 3.55 (1H, m) , 6.4 (1H, d), 6.6 (1H, s), 8.05 (1H, d), 8.2 (1H, d)
MH ⁺ 376 and 377

（Ｄ２３）
室温にてアルゴン下、エタノール（３０ｍｌ）中、Ｎ−（５−メチル−２−ニトロフェニル）−１−［シス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ２２ａ、４４０ｍｇ、１．１７ｍｍｏｌ）の攪拌溶液をラネーニッケル（〜５０ｍｇ）で処理した後、ヒドラジン水和物（２ｍｌ、３０．４ｍｍｏｌ）を滴下し、５０℃で３時間加熱した。この溶液をＫｉｅｓｅｌｇｕｈｒパッドで濾過した後、真空濃縮し、４００ｍｇ（９８％収率）の標題化合物を淡黄色の油状物として得た。
MH⁺ 346および347 Description 23. (2-Amino-5-methylphenyl) {1- [cis-4- (propyloxy) cyclohexyl] -4-piperidinyl} amine (D23)

(D23)
N- (5-Methyl-2-nitrophenyl) -1- [cis-4- (propyloxy) cyclohexyl] -4-piperidinamine (D22a, 440 mg, 1.G in ethanol (30 ml) at room temperature under argon. 17 mmol) was treated with Raney nickel (˜50 mg), hydrazine hydrate (2 ml, 30.4 mmol) was added dropwise and heated at 50 ° C. for 3 hours. The solution was filtered through a Kieselguhr pad and then concentrated in vacuo to give 400 mg (98% yield) of the title compound as a pale yellow oil.
MH ⁺ 346 and 347

（Ｄ２４）
室温にてアルゴン下、エタノール（２０ｍｌ）中、Ｎ−（５−メチル−２−ニトロフェニル）−１−［トランス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ２２ｂ、３４０ｍｇ、０．９ｍｍｏｌ）の攪拌懸濁液をラネーニッケル（〜３０ｍｇ）で処理した後、ヒドラジン水和物（０．２８ｍｌ、９．５ｍｍｏｌ）を滴下し、５０℃で３時間加熱した。この溶液をＫｉｅｓｅｌｇｕｈｒパッドで濾過した後、真空濃縮し、３１０ｍｇ（９９％収率）の標題化合物を淡黄色の油状物として得た。
MH⁺ 346および347 Description 24. (2-Amino-5-methylphenyl) {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} amine (D24)

(D24)
N- (5-methyl-2-nitrophenyl) -1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinamine (D22b, 340 mg, 0. 2) in ethanol (20 ml) under argon at room temperature. 9 mmol) was treated with Raney nickel (˜30 mg), and then hydrazine hydrate (0.28 ml, 9.5 mmol) was added dropwise and heated at 50 ° C. for 3 hours. The solution was filtered through a Kieselguhr pad and then concentrated in vacuo to give 310 mg (99% yield) of the title compound as a pale yellow oil.
MH ⁺ 346 and 347

（Ｄ２５）
室温にてアルゴン下、１，４−ジオキサスピロ［４．５］デカン−８−オール（Ｄ１、５．０ｇ、０．０３２ｍｏｌ）、２−ヨードプロパン（２５ｍｌ）および酸化銀（Ｉ）（１４ｇ、０．０６０ｍｏｌ）の混合物を暗所で６日間攪拌した後、６日間放置した。この混合物をジエチルエーテル（４０ｍｌ）で処理し、Ｋｉｅｓｅｌｇｕｈｒで濾過し、ジエチルエーテルでよく洗浄した。濾液を真空濃縮し、残渣をヘキサン（１５０ｍｌ）に溶解し、水（１５０ｍｌ）で洗浄した後、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、ケタールの加水分解に由来する４−［（１−メチルエチル）オキシ］シクロヘキサノンとともにおよそ８０％の標題化合物を含有する無色の油状物（４．８９ｇ）を得た。この混合物を精製せずに次の工程に用いた。
¹H NMR δ(CDCl₃, 400 MHz): 1.13 (6H, d), 1.5-1.59 (2H, m), 1.60-1.74 (2H, m), 1.75-1.88 (4H, m), 3.43-3.50 (1H, m), 3.62-3.72 (1H, m), 3.90-4.00 (4H, m) Description 25.8-[(1-Methylethyl) oxy] -1,4-dioxaspiro [4.5] decane (D25)

(D25)
1,4-Dioxaspiro [4.5] decan-8-ol (D1, 5.0 g, 0.032 mol), 2-iodopropane (25 ml) and silver (I) oxide (14 g, 0) under argon at room temperature. .060 mol) was stirred in the dark for 6 days and then left for 6 days. The mixture was treated with diethyl ether (40 ml), filtered through Kieselguhr and washed well with diethyl ether. The filtrate was concentrated in vacuo and the residue was dissolved in hexane (150 ml), washed with water (150 ml), then dried (Na ₂ SO ₄ ), concentrated in vacuo and 4-[(1 A colorless oil (4.89 g) containing approximately 80% of the title compound with -methylethyl) oxy] cyclohexanone was obtained. This mixture was used in the next step without purification.
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.13 (6H, d), 1.5-1.59 (2H, m), 1.60-1.74 (2H, m), 1.75-1.88 (4H, m), 3.43-3.50 ( 1H, m), 3.62-3.72 (1H, m), 3.90-4.00 (4H, m)

（Ｄ２６）
室温にてアルゴン下、テトラヒドロフラン（１０ｍｌ）中、８−［（１−メチルエチル）オキシ］−１，４−ジオキサスピロ［４．５］デカンおよび４−［（１−メチルエチル）オキシ］シクロヘキサノン（〜４：１）（Ｄ２５、４．８９ｇ、〜０．０２５ｍｏｌ）の混合物の溶液を５Ｍ ＨＣｌ（５０ｍｌ）で処理し、１８時間よく攪拌した。この反応混合物を水（１５０ｍｌ）で処理し、ジクロロメタン（２×８０ｍｌ）で抽出した。合わせた抽出液をブラインで洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、標題化合物を無色の油状物として得た（３．９ｇ、１００％）。
¹H NMR δ(CDCl₃, 400 MHz): 1.19 (6H, d), 1.88-2.08 (4H, m), 2.22-2.32 (2H, m), 2.54-2.65 (2H, m), 3.70-3.84 (2H, m) Description 26.4-[(1-methylethyl) oxy] cyclohexanone (D26)

(D26)
8-[(1-Methylethyl) oxy] -1,4-dioxaspiro [4.5] decane and 4-[(1-methylethyl) oxy] cyclohexanone (˜˜) in tetrahydrofuran (10 ml) under argon at room temperature. 4: 1) A solution of a mixture of (D25, 4.89 g, .about.0.025 mol) was treated with 5M HCl (50 ml) and stirred well for 18 hours. The reaction mixture was treated with water (150 ml) and extracted with dichloromethane (2 × 80 ml). The combined extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a colorless oil (3.9 g, 100%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.19 (6H, d), 1.88-2.08 (4H, m), 2.22-2.32 (2H, m), 2.54-2.65 (2H, m), 3.70-3.84 ( 2H, m)

Ｄ２７ａ Ｄ２７ｂ
室温にてアルゴン下、ジクロロメタン（１００ｍｌ）中、４−［（１−メチルエチル）オキシ］シクロヘキサノン（Ｄ２６、３．９ｇ、０．０２５ｍｏｌ）の攪拌溶液を４−ピペリジニルカルバミン酸１，１−ジメチルエチル（５．０ｇ、０．０２５ｍｏｌ）で処理した後、トリアセトキシ水素化ホウ素ナトリウム（７．４ｇ、０．０３５ｍｏｌ）１０分かけて少量ずつ加えた。攪拌を助けるためにさらなるジクロロメタン（５０ｍｌ）を加え、これを室温で１８時間続けた。この反応混合物をメタノール（５ｍｌ）で注意深く処理し、２０分間攪拌した後、２％Ｎａ_２ＣＯ_３溶液（２００ｍｌ）を加え、この混合物をジクロロメタン（２×１５０ｍｌ）で抽出した。合わせた抽出液をブラインで洗浄した後、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残った黄色油状物（８．６ｇ）を６０〜８０石油エーテル（８０ｍｌ）でトリチュレートしたところ、すぐに白色固体の結晶化が起こった。これを濾別し、６０〜８０石油エーテルで洗浄し、乾燥させた後、９：１の６０〜８０石油エーテル／ジクロロメタンから再結晶させ、標題化合物のトランス異性体（Ｄ２７ｂ）を白色固体として得た（０．８５ｇ）。
¹H NMR δ(CDCl₃, 400 MHz): 1.12 (6H, d), 1.18-1.50 (6H, m), 1.44 (9H, s), 1.80-2.05 (6H, m), 2.20-2.32 (3H, m), 2.80-2.90 (2H, m), 3.15-3.26 (1H, m), 3.38-3.50 (1H, m), 3.64-3.73 (1H, m), 4.37-4.47 (1H, m) Description 27. 1,1-dimethylethyl (D27a) and (1- {trans-4-[(1-methylethyl)) (1- {cis-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) carbamate ) Oxy] cyclohexyl} -4-piperidinyl) 1,1-dimethylethyl carbamate (D27b)

D27a D27b
A stirred solution of 4-[(1-methylethyl) oxy] cyclohexanone (D26, 3.9 g, 0.025 mol) in dichloromethane (100 ml) at room temperature under argon was treated with 4-piperidinylcarbamic acid 1,1- After treatment with dimethylethyl (5.0 g, 0.025 mol), sodium triacetoxyborohydride (7.4 g, 0.035 mol) was added in small portions over 10 minutes. Additional dichloromethane (50 ml) was added to aid stirring and this was continued at room temperature for 18 hours. The reaction mixture was carefully treated with methanol (5 ml) and stirred for 20 minutes, then 2% Na ₂ CO ₃ solution (200 ml) was added and the mixture was extracted with dichloromethane (2 × 150 ml). The combined extracts were washed with brine, then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The remaining yellow oil (8.6 g) was triturated with 60-80 petroleum ether (80 ml) and a white solid crystallized immediately. This was filtered off, washed with 60-80 petroleum ether, dried and recrystallized from 9: 1 60-80 petroleum ether / dichloromethane to give the trans isomer of the title compound (D27b) as a white solid. (0.85 g).
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.12 (6H, d), 1.18-1.50 (6H, m), 1.44 (9H, s), 1.80-2.05 (6H, m), 2.20-2.32 (3H, m), 2.80-2.90 (2H, m), 3.15-3.26 (1H, m), 3.38-3.50 (1H, m), 3.64-3.73 (1H, m), 4.37-4.47 (1H, m)

  Concentration of the initial crystallization mother liquor in vacuo gave 7.3 g of a yellow oil containing the title compound cis isomer (D27a) as a ˜4: 1 mixture with the trans isomer.

（Ｄ２８）
室温にてアルゴン下、ジクロロメタン（１０ｍｌ）中、（１−｛トランス−４−［（１−メチルエチル）オキシ］シクロヘキシル｝−４−ピペリジニル）カルバミン酸１，１−ジメチルエチル（Ｄ２７ｂ、８５０ｍｇ、２．５ｍｍｏｌ）の攪拌溶液を４Ｍ ＨＣｌ／ジオキサン（５ｍｌ；２０ｍｍｏｌ）で処理し、１８時間維持した後、真空濃縮した。残渣をジエチルエーテル（２０ｍｌ）で処理し、５分間攪拌した後、固体を濾別し、ジエチルエーテルで洗浄し、その後、乾燥させ、標題化合物を白色固体として得た（７３０ｍｇ、９３％）。
¹H NMR δ(d⁶DMSO, 400 MHz): 1.05 (6H, d), 1.08-1.22 (2H, m), 1.43-1.60 (2H, m), 1.93-2.20 (8H, m), 2.98-3.15 (3H, m), 3.20-3.55 (5H, m), 3.62-3.72 (1H, m), 8.46 & 8.60 (together 3H, 2 x brs), 10.84 & 10.95 (together 1H, 2 x brs) Description 28.1- {trans-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidineamine dihydrochloride (D28)

(D28)
1,1-dimethylethyl (D27b, 850 mg, 2) (1- {trans-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) carbamate in dichloromethane (10 ml) at room temperature under argon .5 mmol) was treated with 4M HCl / dioxane (5 ml; 20 mmol) and maintained for 18 hours before being concentrated in vacuo. The residue was treated with diethyl ether (20 ml) and stirred for 5 minutes before the solid was filtered off, washed with diethyl ether and then dried to give the title compound as a white solid (730 mg, 93%).
¹ H NMR δ (d ⁶ DMSO, 400 MHz): 1.05 (6H, d), 1.08-1.22 (2H, m), 1.43-1.60 (2H, m), 1.93-2.20 (8H, m), 2.98-3.15 (3H, m), 3.20-3.55 (5H, m), 3.62-3.72 (1H, m), 8.46 & 8.60 (together 3H, 2 x brs), 10.84 & 10.95 (together 1H, 2 x brs)

（Ｄ２９）
室温にてアルゴン下、ジクロロメタン（５０ｍｌ）中、（１−｛シス−４−［（１−メチルエチル）オキシ］シクロヘキシル｝−４−ピペリジニル）カルバミン酸シス／トランス１，１−ジメチルエチル（Ｄ２７ａ、〜４：１シス：トランス、７．３ｇ、０．０２１ｍｏｌ）の溶液を４Ｍ ＨＣｌ／ジオキサン（３０ｍｌ；０．１２ｍｏｌ）で処理し、１８時間よく攪拌した。白色沈殿を含有するこの混合物を真空濃縮し、残渣をジエチルエーテル（１００ｍｌ）で処理し、５分間よく攪拌した後、固体を濾別し、ジエチルエーテルで洗浄し、乾燥させ、標題化合物（シス：トランス異性体の〜４：１混合物）を白色固体として得た（４．４６ｇ、６７％）。 Description 29. Cis / trans-1- {4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidineamine dihydrochloride (D29)

(D29)
(1- {cis-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) carbamate cis / trans 1,1-dimethylethyl (D27a, in dichloromethane (50 ml) at room temperature under argon A solution of ˜4: 1 cis: trans, 7.3 g, 0.021 mol) was treated with 4M HCl / dioxane (30 ml; 0.12 mol) and stirred well for 18 hours. The mixture containing a white precipitate was concentrated in vacuo and the residue was treated with diethyl ether (100 ml) and stirred well for 5 minutes before the solid was filtered off, washed with diethyl ether and dried to give the title compound (cis: A ˜4: 1 mixture of trans isomers) was obtained as a white solid (4.46 g, 67%).

（Ｄ３０）
アルゴン下、ジメチルホルムアミド（５ｍｌ）中、３−フルオロ−４−ニトロトルエン（１５５ｍｇ、１．０ｍｍｏｌ）、ジイソプロピルエチルアミン（０．５３ｍｌ、３．０ｍｍｏｌ）および１−｛トランス−４−［（１−メチルエチル）オキシ］シクロヘキシル｝−４−ピペリジンアミン二塩酸塩（Ｄ２８、２５０ｍｇ、０．８０ｍｍｏｌ）の攪拌混合物をマイクロ波反応装置にて２００℃で１０分間加熱した。得られた混合物を真空濃縮し、残渣を１０％Ｎａ_２ＣＯ_３溶液で処理し、ジクロロメタンで抽出した。抽出液を乾燥させ、真空濃縮し、残渣をＳＣＸカートリッジ（１０ｇ）に乗せ、これをジクロロメタン、次いでメタノールで洗浄して非塩基性夾雑物を除去した後、２Ｍ ＮＨ_３／メタノールで洗浄して生成物を取り出した。０〜５％メタノール／ジクロロメタンで溶出するシリカゲル（２０ｇ）でのクロマトグラフィーによるさらなる精製で、標題化合物を暗橙色固体として得た（２２０ｍｇ、７４％）。
¹H NMR δ(CDCl₃, 400 MHz): 1.14 (6H, d), 1.20-1.38 (4H, m), 1.58-1.72 (2H, m), 1.86-1.96 (2H, m), 2.00-2.12 (4H, m), 2.27-2.37 (1H, m), 2.33 (3H, s), 2.38-2.48 (2H, m), 2.83-2.93 (2H, m), 3.19-3.29 (1H, m), 3.50-3.60 (1H, m), 3.65-3.77 (1H, m), 6.43 (1H, dd), 6.61 (1H, s), 8.06 (1H, d), 8.19 (1H, d) Description 30.1- {trans-4-[(1-methylethyl) oxy] cyclohexyl} -N- (5-methyl-2-nitrophenyl) -4-piperidinamine (D30)

(D30)
3-Fluoro-4-nitrotoluene (155 mg, 1.0 mmol), diisopropylethylamine (0.53 ml, 3.0 mmol) and 1- {trans-4-[(1-methylethyl) in dimethylformamide (5 ml) under argon. ) Oxy] cyclohexyl} -4-piperidineamine dihydrochloride (D28, 250 mg, 0.80 mmol) was heated in a microwave reactor at 200 ° C. for 10 minutes. The resulting mixture was concentrated in vacuo and the residue was treated with 10% Na ₂ CO ₃ solution and extracted with dichloromethane. The extract was dried and concentrated in vacuo, and the residue was loaded onto an SCX cartridge (10 g), which was washed with dichloromethane and then methanol to remove non-basic contaminants and then washed with 2M NH ₃ / methanol. The thing was taken out. Further purification by chromatography on silica gel (20 g) eluting with 0-5% methanol / dichloromethane gave the title compound as a dark orange solid (220 mg, 74%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.14 (6H, d), 1.20-1.38 (4H, m), 1.58-1.72 (2H, m), 1.86-1.96 (2H, m), 2.00-2.12 ( 4H, m), 2.27-2.37 (1H, m), 2.33 (3H, s), 2.38-2.48 (2H, m), 2.83-2.93 (2H, m), 3.19-3.29 (1H, m), 3.50- 3.60 (1H, m), 3.65-3.77 (1H, m), 6.43 (1H, dd), 6.61 (1H, s), 8.06 (1H, d), 8.19 (1H, d)

（Ｄ３１）
室温にてアルゴン下、エタノール（１５ｍｌ）中、１−｛トランス−４−［（１−メチルエチル）オキシ］シクロヘキシル｝−Ｎ−（５−メチル−２−ニトロフェニル）−４−ピペリジンアミン（Ｄ３０、２２０ｍｇ、０．５９ｍｍｏｌ）の攪拌懸濁液をラネーニッケル（〜２０ｍｇ）で処理した後、ヒドラジン水和物（０．１８ｍｌ、５．０ｍｍｏｌ）を滴下した。この混合物を室温で３時間維持した後、Ｋｉｅｓｅｌｇｕｈｒで濾過して触媒を除去し、濾液を真空濃縮し、標題化合物を淡灰色固体として得た（１８７ｍｇ、９２％）。
¹H NMR δ(CDCl₃, 400 MHz): 1.14 (6H, d), 1.18-1.37 (4H, m), 1.42-1.56 (2H, m), 1.87-1.97 (2H, m), 1.98-2.12 (4H, m), 2.25 (3H, s), 2.27-2.42 (3H, m), 2.85-2.95 (2H, m), 3.00-3.30 (4H, br m), 3.63-3.75 (1H, m), 6.43-6.49 (2H, m), 6.62 (1H, dd) Description 31. (2-Amino-5-methylphenyl) (1- {trans-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) amine (D31)

(D31)
1- {trans-4-[(1-methylethyl) oxy] cyclohexyl} -N- (5-methyl-2-nitrophenyl) -4-piperidineamine (D30) in ethanol (15 ml) under argon at room temperature. , 220 mg, 0.59 mmol) was treated with Raney nickel (˜20 mg), followed by the dropwise addition of hydrazine hydrate (0.18 ml, 5.0 mmol). The mixture was maintained at room temperature for 3 hours, then filtered through Kieselguhr to remove the catalyst, and the filtrate was concentrated in vacuo to give the title compound as a light gray solid (187 mg, 92%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.14 (6H, d), 1.18-1.37 (4H, m), 1.42-1.56 (2H, m), 1.87-1.97 (2H, m), 1.98-2.12 ( 4H, m), 2.25 (3H, s), 2.27-2.42 (3H, m), 2.85-2.95 (2H, m), 3.00-3.30 (4H, br m), 3.63-3.75 (1H, m), 6.43 -6.49 (2H, m), 6.62 (1H, dd)

（Ｄ３２）
４−ピペリジニルカルバミン酸１，１−ジメチルエチル（１．０ｇ）、４−（メチルオキシ）シクロヘキサノン（Ｄ３；６４０ｍｇ；５ｍｍｏｌ）および２．５Ｍ塩酸（２．０ｍｌ；５ｍｍｏｌ）の混合物にシアン化カリウム（３２０ｍｇ；５ｍｍｏｌ）を加えた。室温で２時間、この混合物を水とジクロロメタンとで分液した。乾燥および蒸発させ、標題化合物をシスおよびトランス異性体の混合物として得た（１．１ｇ）。 Description 32. [1- (1-Cyano-4-methoxycyclohexyl) -4-piperidinyl] carbamic acid cis / trans-1,1-dimethylethyl (D32)

(D32)
To a mixture of 1,1-dimethylethyl 4-piperidinylcarbamate (1.0 g), 4- (methyloxy) cyclohexanone (D3; 640 mg; 5 mmol) and 2.5 M hydrochloric acid (2.0 ml; 5 mmol) was added potassium cyanide ( 320 mg; 5 mmol) was added. The mixture was partitioned between water and dichloromethane for 2 hours at room temperature. Drying and evaporation gave the title compound as a mixture of cis and trans isomers (1.1 g).

（Ｄ３３）
テトラヒドロフラン（２５ｍｌ）中、［１−（１−シアノ−４−メトキシシクロヘキシル）−４−ピペリジニル］カルバミン酸シス／トランス−１，１−ジメチルエチル（Ｄ３２、異性体の混合物）（１．１ｇ；３．３ｍｍｏｌ）の溶液に、臭化メチルマグネシウム（ジエチルエーテル中３Ｍ溶液５．０ｍｌ）を加えた。室温で２時間後、この溶液をロッシェル塩水溶液とジクロロメタンとで分液した。乾燥させ、蒸発させ、クロマトグラフィー（５０ｇシリカ、ジクロロメタン中０〜１０％のメタノール）により、標題化合物をシスおよびトランス異性体の混合物として得た（４００ｍｇ）。 Description 33. [1- (1-Methyl-4-methoxycyclohexyl) -4-piperidinyl] carbamic acid cis / trans-1,1-dimethylethyl (D33)

(D33)
[1- (1-Cyano-4-methoxycyclohexyl) -4-piperidinyl] carbamic acid cis / trans-1,1-dimethylethyl (D32, mixture of isomers) (1.1 g; 3) in tetrahydrofuran (25 ml) .3 mmol) was added methylmagnesium bromide (5.0 ml of a 3M solution in diethyl ether). After 2 hours at room temperature, the solution was partitioned between an aqueous Rochelle salt solution and dichloromethane. Drying, evaporation and chromatography (50 g silica, 0-10% methanol in dichloromethane) gave the title compound as a mixture of cis and trans isomers (400 mg).

（Ｄ３４）
｛１−［１−メチル−４−（メチルオキシ）シクロヘキシル］−４−ピペリジニル｝カルバミン酸シス／トランス−１，１−ジメチルエチル（Ｄ３３、３６０ｍｇ、１．１ｍｍｏｌ）をジクロロメタン（５ｍｌ）に溶解し、室温にてＨＣｌ（１０当量、１１ｍｍｏｌ、１，４−ジオキサン中４Ｍ溶液２．８ｍｌ）を加え、この混合物を室温で一晩攪拌した。その後、溶媒を蒸発させて粗生成物を得、これをＳＣＸにより精製し、標題化合物２００ｍｇ、６０％を得た。
¹H NMR δ(d⁶DMSO, 400 MHz) 0.750 (3H, d), 1.100(3H, m), 1.522 (9H, m), 1.838 (1H, d), 1.973 (2H, m), 2.433 (1H, m), 2.770 (2H, t), 3.121 (1H, m), 3.195 (3H, d), 3.329 (1H, s br) Description 34. Cis / trans-1- [1-methyl-4- (methyloxy) cyclohexyl] -4-piperidineamine (D34)

(D34)
{1- [1-Methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} carbamic acid cis / trans-1,1-dimethylethyl (D33, 360 mg, 1.1 mmol) was dissolved in dichloromethane (5 ml). HCl (10 eq, 11 mmol, 2.8 ml of 4M solution in 1,4-dioxane) was added at room temperature and the mixture was stirred at room temperature overnight. The solvent was then evaporated to give the crude product, which was purified by SCX to give the title compound 200 mg, 60%.
¹ H NMR δ (d ⁶ DMSO, 400 MHz) 0.750 (3H, d), 1.100 (3H, m), 1.522 (9H, m), 1.838 (1H, d), 1.973 (2H, m), 2.433 (1H , m), 2.770 (2H, t), 3.121 (1H, m), 3.195 (3H, d), 3.329 (1H, s br)

（Ｄ３５ａ） （Ｄ３５ｂ）
２−フルオロ−４−メチル−１−ニトロベンゼン（１当量、１３６ｍｇ）、シス／トランス１−［１−メチル−４−（メチルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ３４、１当量、２００ｍｇ、０．８８ｍｍｏｌ）、ヒューニッヒの塩基ジイソプロピルエチルアミン（１当量、１５０μｌ）を全て室温でジメチルホルムアミド（３ｍｌ）に溶解し、この混合物を１００℃で一晩還流した。次に、この粗混合物を室温まで冷却し、ブラインに注ぎ、この水溶液を酢酸エチルで抽出し（３回）、有機液をブラインと水で交互に洗浄した。有機液を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させて粗生成物を得、これをシリカカラムでのクロマトグラフィー（メタノール−ＮＨ_３−ジクロロメタン）により精製し、２つの独立した異性体（シス、Ｄ３５ａ、１１８ｍｇ）および（トランス、Ｄ３５ｂ、６１ｍｇ）を得た（総収率５６％）。Ｍ^＋＋Ｈ＝３６２ Description 35. Cis and trans-1- [1-methyl-4- (methyloxy) cyclohexyl] -N- (5-methyl-2-nitrophenyl) -4-piperidinamine (cis = D35a, trans = D35b)

(D35a) (D35b)
2-fluoro-4-methyl-1-nitrobenzene (1 eq, 136 mg), cis / trans 1- [1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinamine (D34, 1 eq, 200 mg, 0 .88 mmol), Hunig's base diisopropylethylamine (1 eq, 150 μl) were all dissolved in dimethylformamide (3 ml) at room temperature and the mixture was refluxed at 100 ° C. overnight. The crude mixture was then cooled to room temperature, poured into brine, the aqueous solution was extracted with ethyl acetate (3 times), and the organic solution was washed with brine and water alternately. The organic were combined, dried over Na ₂ SO _4, filtered and the solvent was evaporated to give a crude product, which was purified by chromatography on a silica column (methanol -NH 3 _- dichloromethane) to give two independent Isomers (cis, D35a, 118 mg) and (trans, D35b, 61 mg) were obtained (total yield 56%). M ⁺ + H = 362

（Ｄ３６）
１−［シス−１−メチル−４−（メチルオキシ）シクロヘキシル］−Ｎ−（５−メチル−２−ニトロフェニル）−４−ピペリジンアミン（Ｄ３５ａ、１１８ｍｇ、０．３２７ｍｍｏｌ）をエタノール（８ｍｌ）に溶解し、室温にてラネーニッケル（５０％水性懸濁液０．３ｍｌ）を加え、この混合物を５０℃に加熱し、５０℃でヒドラジン水和物（１０当量、３．２ｍｍｏｌ、０．１ｍｌ）を滴下した。ＴＬＣにより出発材料が見られなくなるまで、反応物を５０℃で攪拌した。この混合物を室温まで冷却し、セライトで濾過した後、溶媒を蒸発させ、標題化合物を得た（９１ｍｇ、８４％）。Ｍ^＋＋Ｈ＝３３２ Description 36. (2-Amino-5-methylphenyl) {1- [cis-1-methyl-4- (methyloxy) -cyclohexyl] -4-piperidinyl} amine (D36)

(D36)
1- [cis-1-methyl-4- (methyloxy) cyclohexyl] -N- (5-methyl-2-nitrophenyl) -4-piperidineamine (D35a, 118 mg, 0.327 mmol) in ethanol (8 ml) Dissolve and add Raney nickel (0.3 ml of 50% aqueous suspension) at room temperature, heat the mixture to 50 ° C. and add hydrazine hydrate (10 eq, 3.2 mmol, 0.1 ml) at 50 ° C. It was dripped. The reaction was stirred at 50 ° C. until no starting material was seen by TLC. The mixture was cooled to room temperature and filtered through celite, then the solvent was evaporated to give the title compound (91 mg, 84%). M ⁺ + H = 332

（Ｄ３７）
１−［トランス−１−メチル−４−（メチルオキシ）シクロヘキシル］−Ｎ−（５−メチル−２−ニトロフェニル）−４−ピペリジンアミン（Ｄ３５ｂ、６０ｍｇ、０．１６６ｍｍｏｌ）をエタノール（４ｍｌ）に溶解し、室温にてラネーニッケル（５０％水性懸濁液０．２ｍｌ）を加え、この混合物を５０℃に加熱し、５０℃でヒドラジン水和物（１０当量、１．６ｍｍｏｌ、０．０５ｍｌ）を滴下した。ＴＬＣにより出発材料が見られなくなるまで、反応物を５０℃で攪拌した。この混合物を室温まで冷却し、セライトで濾過した後、溶媒を蒸発させ、標題化合物を得た（３０ｍｇ、５５％）。Ｍ^＋＋Ｈ＝３３２ Description 37. (2-Amino-5-methylphenyl) {1- [trans-1-methyl-4- (methyloxy) -cyclohexyl] -4-piperidinyl} amine (D37)

(D37)
1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -N- (5-methyl-2-nitrophenyl) -4-piperidineamine (D35b, 60 mg, 0.166 mmol) in ethanol (4 ml) Dissolve and add Raney nickel (0.2 ml of 50% aqueous suspension) at room temperature, heat the mixture to 50 ° C. and add hydrazine hydrate (10 eq, 1.6 mmol, 0.05 ml) at 50 ° C. It was dripped. The reaction was stirred at 50 ° C. until no starting material was seen by TLC. The mixture was cooled to room temperature and filtered through celite, then the solvent was evaporated to give the title compound (30 mg, 55%). M ⁺ + H = 332

（Ｄ３８）
アルゴン下、ジメチルホルムアミド（８ｍｌ）中、３−フルオロ−４−ニトロトルエン（２５０ｍｇ、１．６ｍｍｏｌ）、ジイソプロピルエチルアミン（０．８６ｍｌ、４．８ｍｍｏｌ）およびシス／トランス−１−｛４−［（１−メチルエチル）オキシ］シクロヘキシル｝−４−ピペリジンアミン二塩酸塩（Ｄ２９、〜４：１シス／トランス、４００ｍｇ、１．３ｍｍｏｌ）の攪拌混合物をマイクロ波反応装置にて２００℃で１２分間加熱した。得られた混合物を真空濃縮し、残渣を１０％Ｎａ_２ＣＯ_３溶液で処理し、ジクロロメタンで抽出した。抽出液を乾燥させ、真空濃縮し、残渣をＳＣＸカートリッジ（２０ｇ）に乗せ、これをジクロロメタン、次いでメタノールで溶出して非塩基性夾雑物を除去した後、２Ｍ ＮＨ_３／メタノールで溶出して生成物を取り出した。この生成物溶液を真空濃縮し、残渣を、０〜２０％酢酸エチル／ヘキサンで溶出するＢｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカカラム（１００ｇ）でのクロマトグラフィーに付し、標題化合物を最も速く溶出する異性体として得た。これは橙色油状物として得られた（１８６ｍｇ、３８％）。
¹HNMR δ(CDCl₃, 400 MHz): 1.14 (6H, d), 1.33-1.46 (2H, m), 1.52-1.78 (6H, m), 1.80-1.96 (2H, m), 2.02-2.12 (2H, m), 2.28-2.40 (1H, m), 2.33 (3H, s), 2.40-2.50 (2H, m), 2.82-2.93 (2H, m), 3.48-3.68 (3H, m), 6.42 (1H, dd), 6.62 (1H, s), 8.05 (1H, d), 8.19 (1H, d) Description 38.1- {cis-4-[(1-methylethyl) oxy] cyclohexyl} -N- (5-methyl-2-nitrophenyl) -4-piperidinamine (D38)

(D38)
3-Fluoro-4-nitrotoluene (250 mg, 1.6 mmol), diisopropylethylamine (0.86 ml, 4.8 mmol) and cis / trans-1- {4-[(1-) in dimethylformamide (8 ml) under argon. A stirred mixture of (methylethyl) oxy] cyclohexyl} -4-piperidineamine dihydrochloride (D29, ˜4: 1 cis / trans, 400 mg, 1.3 mmol) was heated in a microwave reactor at 200 ° C. for 12 minutes. The resulting mixture was concentrated in vacuo and the residue was treated with 10% Na ₂ CO ₃ solution and extracted with dichloromethane. The extract was dried and concentrated in vacuo, and the residue was loaded onto an SCX cartridge (20 g) which was eluted with dichloromethane and then methanol to remove non-basic contaminants and then eluted with 2M NH ₃ / methanol. The thing was taken out. The product solution is concentrated in vacuo and the residue is chromatographed on a Biotage KP-NH ™ -silica column (100 g) eluting with 0-20% ethyl acetate / hexane to elute the title compound the fastest. As an isomer. This was obtained as an orange oil (186 mg, 38%).
¹ HNMR δ (CDCl ₃ , 400 MHz): 1.14 (6H, d), 1.33-1.46 (2H, m), 1.52-1.78 (6H, m), 1.80-1.96 (2H, m), 2.02-2.12 (2H , m), 2.28-2.40 (1H, m), 2.33 (3H, s), 2.40-2.50 (2H, m), 2.82-2.93 (2H, m), 3.48-3.68 (3H, m), 6.42 (1H , dd), 6.62 (1H, s), 8.05 (1H, d), 8.19 (1H, d)

（Ｄ３９）
室温にてアルゴン下、エタノール（１５ｍｌ）中、１−｛シス−４−［（１−メチルエチル）オキシ］シクロヘキシル｝−Ｎ−（５−メチル−２−ニトロフェニル）−４−ピペリジンアミン（Ｄ３８、１８６ｍｇ、０．５０ｍｍｏｌ）の攪拌懸濁液をラネーニッケル（〜２０ｍｇ）で処理した後、ヒドラジン水和物（０．１５ｍｌ、５．０ｍｍｏｌ）を滴下した。この混合物を室温で２時間維持した後、Ｋｉｅｓｅｌｇｕｈｒで濾過して触媒を除去し、濾液を真空濃縮し、標題化合物を灰色油状物として得た（１７０ｍｇ、９９％）。
¹H NMR δ(CDCl₃, 400 MHz): 1.13 (6H, d), 1.33-1.80 (8H, m), 1.85-1.96 (2H, m), 2.02-2.12 (2H, m), 2.25 (3H, s), 2.29-2.42 (3H, m), 2.88-2.98 (2H, m), 3.05-3.40 (4H, br m), 3.53-3.70 (2H, m), 6.41-6.50 (2H, m), 6.61 (1H, d) Description 39. (2-Amino-5-methylphenyl) (1- {cis-4-[(1-methylethyl) oxy] -cyclohexyl} -4-piperidinyl) amine (D39)

(D39)
1- {cis-4-[(1-methylethyl) oxy] cyclohexyl} -N- (5-methyl-2-nitrophenyl) -4-piperidineamine (D38) in ethanol (15 ml) under argon at room temperature. A stirred suspension of 186 mg, 0.50 mmol) was treated with Raney nickel (˜20 mg), followed by the dropwise addition of hydrazine hydrate (0.15 ml, 5.0 mmol). The mixture was maintained at room temperature for 2 hours, then filtered through Kieselguhr to remove the catalyst and the filtrate was concentrated in vacuo to give the title compound as a gray oil (170 mg, 99%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.13 (6H, d), 1.33-1.80 (8H, m), 1.85-1.96 (2H, m), 2.02-2.12 (2H, m), 2.25 (3H, s), 2.29-2.42 (3H, m), 2.88-2.98 (2H, m), 3.05-3.40 (4H, br m), 3.53-3.70 (2H, m), 6.41-6.50 (2H, m), 6.61 (1H, d)

（Ｄ４０）
室温にて、トランス−４−ヒドロキシシクロヘキシルアミン塩酸塩（６９ｇ；０．４６ｍｏｌ）、炭酸カリウム（１５８ｇ；１．１５ｍｏｌ）および水（１ｌ）の混合物に、Ｎ−エトキシカルボニルフタルイミド（１００ｇ；０．４６ｍｏｌ）を加えた。３時間攪拌した後、標題化合物を濾過により単離し、水、次いで酢酸エチルで洗浄した（９５ｇ）。 Description 40. Trans-N- (4-hydroxycyclohexyl) phthalimide (D40)

(D40)
At room temperature, a mixture of trans-4-hydroxycyclohexylamine hydrochloride (69 g; 0.46 mol), potassium carbonate (158 g; 1.15 mol) and water (1 l) was added to N-ethoxycarbonylphthalimide (100 g; 0.46 mol). ) Was added. After stirring for 3 hours, the title compound was isolated by filtration and washed with water and then ethyl acetate (95 g).

（Ｄ４１）
２０〜３０℃（内部、氷冷）にて、トランスＮ−（４−ヒドロキシシクロヘキシル）フタルイミド（Ｄ４０、９５ｇ；０．３９ｍｏｌ）、イミダゾール（５５ｇ；０．７８ｍｏｌ）およびＤＭＦ（２００ｍｌ）の混合物に、塩化ｔｅｒｔ−ブチルジメチルシリル（６０ｇ；０．３９ｍｏｌ）を少量ずつ加えた。４０℃でさらに３時間攪拌した後、この混合物を水／ヘキサンで分液した。有機層を乾燥および蒸発させ、標題化合物をペンタンから結晶化させた（９２ｇ）。 Description 41. Trans-N- (4-tert-butyldimethylsilyloxycyclohexyl) phthalimide (D41)

(D41)
At 20-30 ° C. (internal, ice-cooled), a mixture of trans N- (4-hydroxycyclohexyl) phthalimide (D40, 95 g; 0.39 mol), imidazole (55 g; 0.78 mol) and DMF (200 ml) Tert-butyldimethylsilyl chloride (60 g; 0.39 mol) was added in small portions. After stirring at 40 ° C. for a further 3 hours, the mixture was partitioned with water / hexane. The organic layer was dried and evaporated and the title compound was crystallized from pentane (92 g).

（Ｄ４２）
氷浴温度で攪拌したアセトニトリル（５００ｍｌ）中、トランス−Ｎ−（４−ｔｅｒｔ−ブチルジメチルシリルオキシシクロヘキシル）フタルイミド（Ｄ４１；５０．０ｇ；０．１４ｍｏｌ）、三臭化ビスマス（６．７ｇ；０．０１５ｍｏｌ）、トリエチルシラン（２７ｍｌ；０．１８ｍｏｌ）の溶液に、アセトニトリル（５０ｍｌ）中、アセトアルデヒド（１０ｍｌ；０．１７ｍｏｌ）を３０分かけて加え、この混合物を一晩室温まで温めた。この混合物を濾過し、得られた灰色固体および濾液を別に後処理した。濾液を蒸発させ、ヘキサンで処理し、標題化合物を白色固体として得た（１６．３５ｇ）。この灰色固体をジクロロメタンで洗浄し、このジクロロメタン抽出液を蒸発させ、残渣をヘキサン（２００ｍｌ）とともに攪拌し、標題化合物の第二の産物を白色固体として得た（１７．４７ｇ）。 Description 42. Trans-N- (4-Ethoxycyclohexyl) phthalimide (D42)

(D42)
Trans-N- (4-tert-butyldimethylsilyloxycyclohexyl) phthalimide (D41; 50.0 g; 0.14 mol), bismuth tribromide (6.7 g; 0) in acetonitrile (500 ml) stirred at ice bath temperature. .015 mol), triethylsilane (27 ml; 0.18 mol) in acetonitrile (50 ml) was added acetaldehyde (10 ml; 0.17 mol) over 30 minutes and the mixture was allowed to warm to room temperature overnight. The mixture was filtered and the resulting gray solid and filtrate were worked up separately. The filtrate was evaporated and treated with hexanes to give the title compound as a white solid (16.35 g). The gray solid was washed with dichloromethane, the dichloromethane extract was evaporated and the residue was stirred with hexane (200 ml) to give the second product of the title compound as a white solid (17.47 g).

（Ｄ４３）
エタノール（３００ｍｌ）およびメタノール（２００ｍｌ）中、トランス−Ｎ−（４−エトキシシクロヘキシル）フタルイミド（Ｄ４２、１６．３５ｇ）、ヒドラジン水和物（１２ｍｌ）の溶液を還流下で３時間攪拌した。溶媒を除去してスラリーを得、これをジエチルエーテルで処理し、濾過した。濾液を蒸発させ、標題化合物をエーテルが混入した粘稠な油状物として得た（８．１６ｇ）。 Description 43. Trans-4-ethoxycyclohexylamine (D43)

(D43)
A solution of trans-N- (4-ethoxycyclohexyl) phthalimide (D42, 16.35 g), hydrazine hydrate (12 ml) in ethanol (300 ml) and methanol (200 ml) was stirred under reflux for 3 hours. Removal of the solvent gave a slurry that was treated with diethyl ether and filtered. The filtrate was evaporated to give the title compound as a viscous oil contaminated with ether (8.16 g).

（Ｄ４４）
２０〜３０℃（内部、氷冷）にて、アセトン（１Ｌ）中、１−エチル−４−ピペリドン（１００ｇ；０．７９ｍｏｌ）の溶液に、ヨードメタン（６５ｍｌ；１．００ｍｏｌ）を少量ずつ加えた。さらに３時間攪拌した後、標題化合物を濾取し、アセトンで洗浄した（１８９ｇ）。 Description 44.1-Ethyl-1-methyl-4-oxopiperidinium iodide (D44)

(D44)
Iodomethane (65 ml; 1.00 mol) was added in portions to a solution of 1-ethyl-4-piperidone (100 g; 0.79 mol) in acetone (1 L) at 20-30 ° C. (internal, ice-cooled). . After further stirring for 3 hours, the title compound was collected by filtration and washed with acetone (189 g).

（Ｄ４５）
１−エチル−４−ピペリドンメチオジド（Ｄ４４、２７ｇ）、トランス−４−エトキシシクロヘキシルアミン（Ｄ４３、８．１６ｇ、０．０６５ｍｏｌ）、炭酸カリウム（１３．５ｇ）、水（１００ｍｌ）およびエタノール（２００ｍｌ）の混合物を８０℃で３時間加熱した後、一晩冷却し。この混合物を重炭酸ナトリウム水溶液とジクロロメタンとで分液した。ジクロロメタン層を分離し、ブラインで洗浄し、溶媒を除去し、標題化合物を琥珀色の油状物として得た（１３．２ｇ）。 Description 45. Trans-1- (4-Ethoxycyclohexyl) -4-piperidone (D45)

(D45)
1-ethyl-4-piperidone methiodide (D44, 27 g), trans-4-ethoxycyclohexylamine (D43, 8.16 g, 0.065 mol), potassium carbonate (13.5 g), water (100 ml) and ethanol (200 ml) of the mixture was heated at 80 ° C. for 3 hours and then cooled overnight. The mixture was partitioned between aqueous sodium bicarbonate and dichloromethane. The dichloromethane layer was separated, washed with brine and the solvent was removed to give the title compound as an amber oil (13.2 g).

（Ｄ４６）
室温のアセトニトリル（５００ｍｌ）中、トランス−Ｎ−（４−ｔｅｒｔ−ブチルジメチルシリルオキシシクロヘキシル）フタルイミド（Ｄ４１、４５ｇ）の溶液を、２０〜３０℃（内部、氷冷）にてトリエチルシラン（２４ｍｌ）、三臭化ビスマス（６ｇ）および（滴下）プロパナール（１１ｍｌ）で順次処理した。さらに３０分後、この溶液を重炭酸ナトリウム水溶液／酢酸エチルで分液した。有機層を乾燥および蒸発させ、標題化合物をペンタンから結晶化させた（２０ｇ）。 Description 46. Trans-N- (4-propoxycyclohexyl) phthalimide (D46)

(D46)
A solution of trans-N- (4-tert-butyldimethylsilyloxycyclohexyl) phthalimide (D41, 45 g) in acetonitrile (500 ml) at room temperature was triethylsilane (24 ml) at 20-30 ° C. (internal, ice-cooled). , Sequentially treated with bismuth tribromide (6 g) and (dropping) propanal (11 ml). After an additional 30 minutes, the solution was partitioned with aqueous sodium bicarbonate / ethyl acetate. The organic layer was dried and evaporated and the title compound was crystallized from pentane (20 g).

（Ｄ４７）
トランス−Ｎ−（４−プロポキシシクロヘキシル）フタルイミド（Ｄ４６、２０ｇ）、ヒドラジン水和物（１５ｍｌ）およびエタノール（４００ｍｌ）の混合物を８０℃で２時間加熱した後、冷却し、濾過した。濾液を蒸発させ、得られた残渣をジエチルエーテルに再溶解し、濾過し、再び蒸発させ、標題化合物を得た（１１ｇ）。 Description 47. Trans-4-propoxycyclohexylamine (D47)

(D47)
A mixture of trans-N- (4-propoxycyclohexyl) phthalimide (D46, 20 g), hydrazine hydrate (15 ml) and ethanol (400 ml) was heated at 80 ° C. for 2 hours, then cooled and filtered. The filtrate was evaporated and the resulting residue was redissolved in diethyl ether, filtered and evaporated again to give the title compound (11 g).

（Ｄ４８）
トランス−４−プロポキシシクロヘキシルアミン（Ｄ４７、１１ｇ）、炭酸カリウム（１ｇ）、水（７５ｍｌ）およびエタノール（１５０ｍｌ）の還流混合物に、１−エチル−４−ピペリドンメチオジド（Ｄ４４、２６ｇ）を３０分かけて加えた後、この混合物を８０℃でさらに３０分間加熱し、その後、冷却し、重炭酸ナトリウム水溶液／ジクロロメタンで分液し、クロマトグラフィー（４０＋Ｍ Ｂｉｏｔａｇｅシリカカラム、０．２Ｍアンモニアを含有するジクロロメタン中０〜１０％のメタノール）により精製し、標題化合物を得た（８ｇ）。 Description 48. Trans-1- (4-propoxycyclohexyl) -4-piperidone (D48)

(D48)
To a refluxing mixture of trans-4-propoxycyclohexylamine (D47, 11 g), potassium carbonate (1 g), water (75 ml) and ethanol (150 ml) is added 1-ethyl-4-piperidone methiodide (D44, 26 g). After addition over 30 minutes, the mixture was heated at 80 ° C. for an additional 30 minutes, then cooled, partitioned with aqueous sodium bicarbonate / dichloromethane and chromatographed (40 + M Biotage silica column, containing 0.2 M ammonia. To 0-10% methanol in dichloromethane) to give the title compound (8 g).

（Ｄ４９）
トランス−１−（４−プロポキシシクロヘキシル）−４−ピペリドン（Ｄ４８、７．５ｇ）、メタノール中２Ｍのアンモニア（１００ｍｌ）および１０％パラジウム炭素ペースト（１００ｍｇ）の混合物を室温にて１８時間、５０ｐｓｉで水素化した後、濾過し、蒸発させた。残渣を二塩酸塩へ変換し、標題化合物をジエチルエーテルから結晶化させた（７．５ｇ）。 Description 49. Trans-1- (4-propoxycyclohexyl) -4-piperidineamine dihydrochloride (D49)

(D49)
A mixture of trans-1- (4-propoxycyclohexyl) -4-piperidone (D48, 7.5 g), 2M ammonia in methanol (100 ml) and 10% palladium carbon paste (100 mg) at room temperature for 18 hours at 50 psi. After hydrogenation, filtered and evaporated. The residue was converted to the dihydrochloride salt and the title compound was crystallized from diethyl ether (7.5 g).

（Ｄ５０）
アルゴン雰囲気下で攪拌した４−ヒドロキシシクロヘキサンカルボン酸エチル（１１８ｇ；０．６８ｍｏｌ）、イミダゾール（１０３ｇ；１．５２ｍｏｌ）およびジメチルホルムアミド（４００ｍｌ）の溶液に、クロロ（１，１−ジメチルエチル）ジメチルシラン（１１５ｇ；０．７６ｍｏｌ）を１時間かけて少量ずつ加えた。若干の発熱が見られ、反応混合物の温度は〜４０℃に上昇した。この混合物を室温で一晩攪拌した後、１０％クエン酸溶液（２Ｌ）に注ぎ、ジエチルエーテルで抽出した（２×８００ｍｌ）。これらのエーテル抽出液を水、ブラインで洗浄した後、乾燥させ（Ｎａ_２ＳＯ_４）、溶媒を除去し、標題化合物を油状物として得た（１９８．４ｇ）。
¹H NMR δ(CDCl₃, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1H, m) 3.5 (0.4H, m) 3.86 (1H, m) 4.1 (1H, m) Description 50.4-{[(1,1-dimethylethyl) (dimethyl) silyl] oxy} cyclohexanecarboxylic acid cis / trans-ethyl (D50)

(D50)
To a solution of ethyl 4-hydroxycyclohexanecarboxylate (118 g; 0.68 mol), imidazole (103 g; 1.52 mol) and dimethylformamide (400 ml) stirred under an argon atmosphere, chloro (1,1-dimethylethyl) dimethylsilane (115 g; 0.76 mol) was added in small portions over 1 hour. A slight exotherm was seen and the temperature of the reaction mixture rose to ˜40 ° C. The mixture was stirred overnight at room temperature, then poured into 10% citric acid solution (2 L) and extracted with diethyl ether (2 × 800 ml). These ether extracts were washed with water, brine, then dried (Na ₂ SO ₄ ) and the solvent removed to give the title compound as an oil (198.4 g).
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85 -2 (3H, m), 2.15-2.3 (1H, m) 3.5 (0.4H, m) 3.86 (1H, m) 4.1 (1H, m)

（Ｄ５１）
４−｛［（１，１−ジメチルエチル）（ジメチル）シリル］オキシ｝シクロヘキサンカルボン酸シス／トランスエチル（Ｄ５０、３５ｇ、１２２ｍｍｏｌ）をＣＨ_３ＣＮ（２５０ｍｌ）およびＥｔ_３ＳｉＨ（１．２当量、１４６ｍｍｏｌ、２３ｍｌ）に溶解し、室温でＢｉＢｒ_３（４％ｍｏｌ、４．９ｍｍｏｌ、２．２ｇ）を滴下した後、２５℃にてアセトアルデヒド（１．２当量、８．２ｍｌ）をゆっくり加えた。この混合物を室温で１時間攪拌した。次に、この混合物を飽和ＮａＨＣＯ_３水溶液に注ぎ、得られた混合物を次にＥｔＯＡｃで抽出した（３回）。有機液を合わせ、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させて粗混合物を得、これをシリカクロマトグラフィー（Ｂｉｏｔａｇｅ ６５ｉカラム、ＥｔＯＡｃ−ｎｈｅｘ）により精製し、標題化合物を得た（２１ｇ、８７％）。
¹H NMR δ(DMSO, 400 MHz): 1.1 (3H, m), 1.15 (3H, m), 1.492-3.212 (10 H, ブロードシグナルと多重項のセットと仮定), 3.312 (2 H, m), 4.041 (2H, m) Description 51.4- (Ethyloxy) cyclohexanecarboxylic acid cis / trans-ethyl (D51)

(D51)
4-{[(1,1-dimethylethyl) (dimethyl) silyl] oxy} cyclohexanecarboxylic acid cis / transethyl (D50, 35 g, 122 mmol) was added to CH ₃ CN (250 ml) and Et ₃ SiH (1.2 eq., 146 mmol, 23 ml), BiBr ₃ (4% mol, 4.9 mmol, 2.2 g) was added dropwise at room temperature, and then acetaldehyde (1.2 eq, 8.2 ml) was slowly added at 25 ° C. The mixture was stirred at room temperature for 1 hour. The mixture was then poured into saturated aqueous NaHCO ₃ and the resulting mixture was then extracted with EtOAc (3 times). The organics were combined, washed with brine, dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated to give a crude mixture that was purified by silica chromatography (Biotage 65i column, EtOAc-nhex). The compound was obtained (21 g, 87%).
¹ H NMR δ (DMSO, 400 MHz): 1.1 (3H, m), 1.15 (3H, m), 1.492-3.212 (10 H, assuming broad signal and multiplet set), 3.312 (2 H, m) , 4.041 (2H, m)

（Ｄ５２）
４−（エチルオキシ）シクロヘキサンカルボン酸シス／トランス−エチル（Ｄ５１、２１ｇ、１０５ｍｍｏｌ）をＭｅＯＨ−ＴＨＦ（１００ｍｌ−１００ｍｌ）に溶解し、室温でＮａＯＨ（５当量、０．５ｍｏｌ、４０ｍｌ、１２．５Ｎ水溶液）をゆっくり加えた。この混合物を室温で一晩攪拌した。次に、ＴＨＦ／ＭｅＯＨを蒸発させ、粗物質をＥｔ_２Ｏで洗浄した。水相を酸性化し、ＥｔＯＡｃで抽出し（２回）、有機液をＮａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させ、標題化合物を淡黄色油状物として得た（１７．３ｇ、９６％）。
¹H NMR δ(DMSO, 400 MHz): 1.1 (3H, m), 1.3-3.201 (10 H, ブロードシグナルと多重項のセットと仮定), 3.417 (2H, m), 12.1 (1H, s ブロード) Description 52. Cis / trans-4- (ethyloxy) cyclohexanecarboxylic acid (D52)

(D52)
4- (Ethyloxy) cyclohexanecarboxylic acid cis / trans-ethyl (D51, 21 g, 105 mmol) was dissolved in MeOH-THF (100 ml-100 ml) and NaOH (5 eq, 0.5 mol, 40 ml, 12.5 N aqueous solution at room temperature. ) Was added slowly. The mixture was stirred at room temperature overnight. The THF / MeOH was then evaporated and the crude material was washed with Et ₂ O. The aqueous phase was acidified and extracted with EtOAc (2 times), the organic solution was dried over _Na 2 SO _4, filtered and the solvent was evaporated to give the title compound as a pale yellow oil (17.3 g, 96 %).
¹ H NMR δ (DMSO, 400 MHz): 1.1 (3H, m), 1.3-3.201 (assuming 10 H, broad signal and multiplet set), 3.417 (2H, m), 12.1 (1H, s broad)

（Ｄ５３）
−２０℃にてアルゴン下、乾燥ＴＨＦ（４００ｍｌ）中、ジイソプロピルアミン（２．３当量、０．２３１ｍｏｌ、３３ｍｌ）の攪拌溶液をヘキサン中２．５Ｍのｎ−ブチルリチウム（２．３当量、９３ｍｌ；０．２３１ｍｏｌ）で１０分かけて処理した後、０℃まで温め、１５分間攪拌した。この混合物を−１０℃まで冷却し、〜５０ｍｌの乾燥ＴＨＦ中、シス／トランス−４−（エチルオキシ）シクロヘキサンカルボン酸（Ｄ５２、１７．３ｇ、０．１ｍｏｌ）の溶液で１０分かけて処理した。得られた黄色溶液を５０℃で２．５時間加熱した後、０℃まで冷却し、ヨードメタン（３当量、０．３ｍｏｌ、１９ｍｌ）で処理した。この混合物を室温まで温め、一晩攪拌した。この混合物を１０℃まで冷却し、１０％クエン酸溶液（２００ｍｌ）で処理した後、溶媒を半分の容量まで蒸発させ、真空濃縮した。残った混合物を水（２００ｍｌ）で希釈し、Ｅｔ_２Ｏで抽出した（２回）。合わせた抽出液を水で洗浄し（１５０ｍｌ×２）、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、真空濃縮し、標題化合物を黄色油状物として得た（１６．２ｇ、８７％、シス：トランス異性体の混合物）。
¹H NMR δ(DMSO, 400 MHz): 1.086 (8H, mと仮定), 1.510 (3H, m), 1.698 (1H, m), 1.781 (1H, m), 2.005 (1H, m), 3.191 (1/2H, m), 3.392 (2H, m), 3.606 (1/2H, m), 12.2 (1H, s br) Description 53. Cis / trans-4- (ethyloxy) -1-methylcyclohexanecarboxylic acid (D53)

(D53)
A stirred solution of diisopropylamine (2.3 eq, 0.231 mol, 33 ml) in dry THF (400 ml) under argon at −20 ° C. was added 2.5M n-butyllithium in hexane (2.3 eq, 93 ml). 0.231 mol) over 10 minutes, then warmed to 0 ° C. and stirred for 15 minutes. The mixture was cooled to −10 ° C. and treated with a solution of cis / trans-4- (ethyloxy) cyclohexanecarboxylic acid (D52, 17.3 g, 0.1 mol) in ˜50 ml of dry THF over 10 minutes. The resulting yellow solution was heated at 50 ° C. for 2.5 hours, then cooled to 0 ° C. and treated with iodomethane (3 eq, 0.3 mol, 19 ml). The mixture was warmed to room temperature and stirred overnight. The mixture was cooled to 10 ° C. and treated with 10% citric acid solution (200 ml), then the solvent was evaporated to half volume and concentrated in vacuo. The remaining mixture was diluted with water (200 ml) and extracted with Et ₂ O (twice). The combined extracts were washed with water (150 ml × 2), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound as a yellow oil (16.2 g, 87%, cis: Mixture of trans isomers).
¹ H NMR δ (DMSO, 400 MHz): 1.086 (assuming 8H, m), 1.510 (3H, m), 1.698 (1H, m), 1.781 (1H, m), 2.005 (1H, m), 3.191 ( 1 / 2H, m), 3.392 (2H, m), 3.606 (1 / 2H, m), 12.2 (1H, s br)

（Ｄ５４）
室温にて、シス／トランス−４−（エチルオキシ）−１−メチルシクロヘキサンカルボン酸（Ｄ５３、１６．２ｇ、８７．１ｍｍｏｌ）を塩化チオニル（１５当量、１．３１ｍｏｌ、〜９５ｍｌ）に溶解し、次に、８５℃で４時間還流させた。次に、この混合物を室温まで冷却し、塩化チオニルをトルエンとの共沸により蒸発させた。残渣をＴＨＦ（１００ｍｌ）に溶解し、Ｎａ_２ＣＯ_３の５％水溶液（５００ｍｌ）で処理し、室温で２０分間攪拌した。水性残渣をＥｔ_２Ｏ（２回）で洗浄した後、酸性化し、ＥｔＯＡｃで抽出した（３回）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、真空濃縮し、標題化合物を得た（６．５ｇ、４０％）。
¹H NMR δ(DMSO, 400 MHz): 1.076 (6H, m), 1.505 (6H, m), 1.693 (2H, m), 3.331 (1H, m), 3.394 (2H, q), 12.1 (1H, s br) Description 54. Trans-4- (Ethyloxy) -1-methylcyclohexanecarboxylic acid (D54)

(D54)
At room temperature, cis / trans-4- (ethyloxy) -1-methylcyclohexanecarboxylic acid (D53, 16.2 g, 87.1 mmol) is dissolved in thionyl chloride (15 eq, 1.31 mol, ˜95 ml) and then At 85 ° C. for 4 hours. The mixture was then cooled to room temperature and thionyl chloride was evaporated azeotropically with toluene. The residue was dissolved in THF (100 ml), treated with 5% aqueous solution of Na ₂ CO ₃ (500 ml) and stirred at room temperature for 20 minutes. The aqueous residue was washed with Et ₂ O (2 times), then acidified and extracted with EtOAc (3 times). The combined extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound (6.5 g, 40%).
¹ H NMR δ (DMSO, 400 MHz): 1.076 (6H, m), 1.505 (6H, m), 1.693 (2H, m), 3.331 (1H, m), 3.394 (2H, q), 12.1 (1H, s br)

（Ｄ５５）
室温にてアルゴン下、トルエン（１２０ｍｌ）中、トランス−４−（エチルオキシ）−１−メチルシクロヘキサンカルボン酸（Ｄ５４、５．５ｇ、２９．５ｍｍｏｌ）の攪拌溶液をトリエチルアミン（１．３当量、３７．７ｍｍｏｌ、５．３ｍｌ）およびアジ化ジフェニルホスホリル（１当量、２９．５ｍｍｏｌ、６．４ｍｌ）で処理し、８５℃で１時間加熱した。この混合物を室温まで冷却した後、１Ｍ ＮａＯＨ溶液（３００ｍｌ）で処理し、Ｅｔ_２Ｏで抽出した（３回）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、真空濃縮し、標題化合物を得た（５ｇ、９４％）。
¹H NMR δ(DMSO, 400 MHz): 1.092 (3H, t), 1.330 (3H, s), 1.487-1.691 (8H, m), 3.392 (2H, q), 3.477 (1H, m) Description 55. Trans-4- (Ethyloxy) -1-isocyanato-1-methylcyclohexane (D55)

(D55)
A stirred solution of trans-4- (ethyloxy) -1-methylcyclohexanecarboxylic acid (D54, 5.5 g, 29.5 mmol) in toluene (120 ml) under argon at room temperature was triethylamine (1.3 eq, 37. 7 mmol, 5.3 ml) and diphenylphosphoryl azide (1 eq, 29.5 mmol, 6.4 ml) and heated at 85 ° C. for 1 h. The mixture was cooled to room temperature and then treated with 1M NaOH solution (300 ml) and extracted with Et ₂ O (3 times). The combined extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound (5 g, 94%).
¹ H NMR δ (DMSO, 400 MHz): 1.092 (3H, t), 1.330 (3H, s), 1.487-1.691 (8H, m), 3.392 (2H, q), 3.477 (1H, m)

（Ｄ５６）
ＴＨＦ（１００ｍｌ）中、トランス−４−（エチルオキシ）−１−イソシアナト−１−メチルシクロヘキサン（Ｄ５５、５．０ｇ、２７．３ｍｍｏｌ）の溶液を５Ｍ ＨＣｌ水溶液（５．５当量、１５０ｍｍｏｌ、３０ｍｌ）で処理し、室温にてアルゴン下で一晩攪拌した後、真空濃縮した。残った半固体をＥｔ_２Ｏでトリチュレートし、標題化合物の第一バッチを白色固体として得た（２．８ｇ）。母液を蒸発させ、ＴＨＦに再溶解し（５０ｍｌ）、５Ｍ ＨＣｌ水溶液（１５ｍｌ）で処理し、この混合物を週末にかけて室温で攪拌した。次に、溶媒を蒸発させ、得られた固体を炉中５０℃で乾燥させた後、Ｅｔ_２Ｏでトリチュレートした。この最終のトリチュレーションにより、さらに６４６ｍｇの標題化合物を得た。
¹H NMR δ(DMSO, 400 MHz): 1.084 (3H, t), 1.256 (3H, s), 1.378 (2H, m), 1.619 (4H, m), 1.847 (2H, m), 3.243 (1H, m), 3.424 (2H, q), 8.090 (3H, br s) Description 56. [Trans-4- (ethyloxy) -1-methylcyclohexyl] amine monohydrochloride (D56)

(D56)
A solution of trans-4- (ethyloxy) -1-isocyanato-1-methylcyclohexane (D55, 5.0 g, 27.3 mmol) in THF (100 ml) was added with 5M aqueous HCl (5.5 eq, 150 mmol, 30 ml). Treat and stir overnight at room temperature under argon before concentrating in vacuo. The remaining semi-solid was triturated with Et ₂ O to give the first batch of title compound as a white solid (2.8 g). The mother liquor was evaporated, redissolved in THF (50 ml), treated with 5M aqueous HCl (15 ml) and the mixture was stirred at room temperature over the weekend. The solvent was then evaporated and the resulting solid was dried in an oven at 50 ° C. and then triturated with Et ₂ O. This final trituration yielded an additional 646 mg of the title compound.
¹ H NMR δ (DMSO, 400 MHz): 1.084 (3H, t), 1.256 (3H, s), 1.378 (2H, m), 1.619 (4H, m), 1.847 (2H, m), 3.243 (1H, m), 3.424 (2H, q), 8.090 (3H, br s)

（Ｄ５７）
室温にてアルゴン下、エタノール（２１６ｍｌ）と水（１０８ｍｌ）の混合物中、［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］アミン一塩酸塩（Ｄ５６、３．４４ｇ、１７．８ｍｍｏｌ）の攪拌溶液を炭酸カリウム（１．１当量、１９．６ｍｍｏｌ、２．７ｇ）、次いで１−エチル−１−メチル−４−オキソピペリジニウムヨージド（Ｄ４４、１．５当量、２６．７ｍｍｏｌ、７．１ｇ）で処理した後、８０℃で２時間加熱した。この混合物を室温まで冷却した後、水性残渣を飽和ＮａＨＣＯ_３溶液で処理し、ジクロロメタンで抽出した（３回）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮して粗化合物を得、これを０〜１０％ＭｅＯＨ／ＮＨ_３／ＤＣＭで溶出するシリカゲルでのクロマトグラフィー（Ｂｉｏｔａｇｅ ６５ｉカラム）に付し、標題化合物を得た（２．３ｇ、５４％）。
¹H NMR δ(DMSO, 400 MHz): 0.855 (3H, s), 1.099 (3H, t), 1.421 (2H, m), 1.544 (4H, m), 1.793 (2H, m), 2.297 (4H, t), 2.726 (4H, t), 3.377-3.430 (3H, t + m) Description 57.1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinone (D57)

(D57)
Stirring of [trans-4- (ethyloxy) -1-methylcyclohexyl] amine monohydrochloride (D56, 3.44 g, 17.8 mmol) in a mixture of ethanol (216 ml) and water (108 ml) under argon at room temperature. The solution was potassium carbonate (1.1 eq, 19.6 mmol, 2.7 g) followed by 1-ethyl-1-methyl-4-oxopiperidinium iodide (D44, 1.5 eq, 26.7 mmol, 7. 1 g) and then heated at 80 ° C. for 2 hours. After the mixture was cooled to room temperature, the aqueous residue was treated with saturated NaHCO ₃ solution and extracted with dichloromethane (3 times). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the crude compound which was chromatographed on silica gel (Biotage 65i column) eluting with 0-10% MeOH / NH ₃ / DCM. To give the title compound (2.3 g, 54%).
¹ H NMR δ (DMSO, 400 MHz): 0.855 (3H, s), 1.099 (3H, t), 1.421 (2H, m), 1.544 (4H, m), 1.793 (2H, m), 2.297 (4H, t), 2.726 (4H, t), 3.377-3.430 (3H, t + m)

（Ｄ５８）
２Ｍ ＮＨ_３／ＭｅＯＨ（２００ｍｌ）中、１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジノン（２．３ｇ、９．６２ｍｍｏｌ）の溶液を１０％Ｐｄ／Ｃ（５１０ｍｇ）で処理し、室温にて一晩初期気圧５０ｐｓｉの水素雰囲気下で振盪した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過して触媒を除去し、濾液を真空濃縮し、遊離塩基の標題化合物を得た。これを１０ｍｌのＨＣｌ（Ｅｔ_２Ｏ中１Ｍ溶液）で処理し、ＭｅＯＨ（２０ｍｌ）中で１０分間攪拌した。次に、溶媒を蒸発させ、標題化合物を白色固体として得た（２．８ｇ、完全に変換）。
¹H NMR δ(DMSO, 250 MHz, at 352.2K): 1.091 (6H, m br), 1.336 (2H, m), 1.695-1.865 (7H, m), 2.067 (2H, d br), 2.531 (1H, br), 3.187-3.317 (6H, ブロードシグナルと多重項のセットと仮定), 3.434 (2H, q), 8.496 (2H, s br) Description 58.1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidineamine dihydrochloride (D58)

(D58)
A solution of 1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinone (2.3 g, 9.62 mmol) in 2M NH ₃ / MeOH (200 ml) was 10% Pd / C (510 mg). And shaken at room temperature overnight under an atmosphere of hydrogen at an initial pressure of 50 psi. The mixture was filtered through Kieselguhr to remove the catalyst and the filtrate was concentrated in vacuo to give the free base title compound. This was treated with 10 ml HCl (1M solution in Et ₂ O) and stirred in MeOH (20 ml) for 10 min. The solvent was then evaporated to give the title compound as a white solid (2.8 g, complete conversion).
¹ H NMR δ (DMSO, 250 MHz, at 352.2K): 1.091 (6H, m br), 1.336 (2H, m), 1.695-1.865 (7H, m), 2.067 (2H, d br), 2.531 (1H , br), 3.187-3.317 (assuming 6H, broad signal and multiplet set), 3.434 (2H, q), 8.496 (2H, s br)

（Ｄ５９）
室温にてアルゴン下、トルエン（４０ｍｌ）中、シス／トランス−４−（エトキシ）−１−メチルシクロヘキサンカルボン酸（Ｄ５３、２．０ｇ、１０．７ｍｍｏｌ）の攪拌溶液をトリエチルアミン（１．９５ｍｌ、１４．０ｍｍｏｌ）およびアジ化ジフェニルホスホリル（２．３ｍｌ、１０．７ｍｍｏｌ）で処理し、８０℃で４５分間加熱した。この混合物を室温まで冷却した後、１Ｍ ＮａＯＨ溶液（５０ｍｌ）およびＥｔ_２Ｏ（５０ｍｌ）で処理し、よく振盪し、有機溶液を分離し、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮して黄色油状物を得（１．７ｇ）、これを０〜１０％ＥｔＯＡｃ／ヘキサンで溶出するシリカゲル（４０ｇ）でのクロマトグラフィーに付した。これにより、低ｒｆ成分としての標題化合物（２１５ｍｇ）を、両異性体を含有する混合画分とともに得た。
¹H NMR (シス異性体) δ(CDCl₃, 400 MHz): 1.20 (3H, t), 1.32-1.50 (5H, m), 1.5-1.66 (2H, m), 1.78-1.96 (4H, m), 3.16-3.26 (1H, m), 3.48-3.58 (2H, q ) Description 59. Cis-4- (ethyloxy) -1-isocyanato-1-methylcyclohexane (D59)

(D59)
A stirred solution of cis / trans-4- (ethoxy) -1-methylcyclohexanecarboxylic acid (D53, 2.0 g, 10.7 mmol) in toluene (40 ml) under argon at room temperature was triethylamine (1.95 ml, 14 0.0 mmol) and diphenylphosphoryl azide (2.3 ml, 10.7 mmol) and heated at 80 ° C. for 45 min. The mixture was cooled to room temperature and then treated with 1M NaOH solution (50 ml) and Et ₂ O (50 ml), shaken well, the organic solution was separated, dried (Na ₂ SO ₄ ) and concentrated in vacuo to a yellow color. An oil was obtained (1.7 g) which was chromatographed on silica gel (40 g) eluting with 0-10% EtOAc / hexane. This gave the title compound (215 mg) as a low rf component along with a mixed fraction containing both isomers.
¹ H NMR (cis isomer) δ (CDCl ₃ , 400 MHz): 1.20 (3H, t), 1.32-1.50 (5H, m), 1.5-1.66 (2H, m), 1.78-1.96 (4H, m) , 3.16-3.26 (1H, m), 3.48-3.58 (2H, q)

（Ｄ６０）
ＴＨＦ（５ｍｌ）中、シス−４−（エチルオキシ）−１−イソシアナト−１−メチルシクロヘキサン（Ｄ５９、２１５ｍｇ、１．１７ｍｍｏｌ）の溶液を５Ｍ ＨＣｌ（１ｍｌ）で処理し、室温で１８時間攪拌した後、真空濃縮し、残渣をトルエンと共沸させて水の痕跡を除去した。残った無色の油状物を真空下で２日間乾燥させた。残った半固体をＥｔ_２Ｏ（５ｍｌ）でトリチュレートし、標題化合物を白色固体として得た（２１３ｍｇ、９４％）。
¹H NMR δ(CDCl₃, 400 MHz): 1.19 (3H, t), 1.50 (3H, s), 1.55-1.77 (4H, m), 1.79-1.91 (2H, m), 2.02-2.15 (2H, m), 3.34-3.40 (1H, m), 3.47 (2H, q), 8.40 (3H, br s) Description 60. [Cis-4- (Ethyloxy) -1-methylcyclohexyl] amine hydrochloride (D60)

(D60)
A solution of cis-4- (ethyloxy) -1-isocyanato-1-methylcyclohexane (D59, 215 mg, 1.17 mmol) in THF (5 ml) was treated with 5M HCl (1 ml) and stirred at room temperature for 18 hours. Concentrate in vacuo and azeotrope the residue with toluene to remove traces of water. The remaining colorless oil was dried under vacuum for 2 days. The remaining semi-solid was triturated with Et ₂ O (5 ml) to give the title compound as a white solid (213 mg, 94%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.19 (3H, t), 1.50 (3H, s), 1.55-1.77 (4H, m), 1.79-1.91 (2H, m), 2.02-2.15 (2H, m), 3.34-3.40 (1H, m), 3.47 (2H, q), 8.40 (3H, br s)

（Ｄ６１）
室温にてアルゴン下、エタノール（１２ｍｌ）と水（６ｍｌ）の混合物中、［シス−４−（エチルオキシ）−１−メチルシクロヘキシル］アミン塩酸塩（Ｄ６０、２００ｍｇ、１．０３ｍｍｏｌ）の攪拌溶液を炭酸カリウム（１５６ｍｇ、１．１３ｍｍｏｌ）、次いで１−エチル−１−メチル−４−オキソピペリジニウムヨージド（Ｄ４４、４０４ｍｇ、１．５０ｍｍｏｌ）で処理した後、８０℃で１．５時間加熱した。この混合物を冷却し、およそ７ｍｌまで真空濃縮した後、ＮａＨＣＯ_３溶液（１５ｍｌ）で処理し、ジクロロメタン（３×２０ｍｌ）で抽出した。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、褐色油状物を得（２５０ｍｇ）、これを０〜５％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルでのクロマトグラフィーに付し、標題化合物を黄色油状物として得た（１４０ｍｇ、５７％）。
¹H NMR δ(CDCl₃, 400 MHz): 0.89 (3H, s), 1.13-1.27 (2H, m), 1.20 (3H, t), 1.68-1.80 (4H, m), 1.95-2.05 (2H, m), 2.40-2.47 (4H, m), 2.76-2.83 (4H, m), 3.25-3.33 (1H, m), 3.52 (2H, q) Description 61.1- [cis-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinone (D61)

(D61)
A stirred solution of [cis-4- (ethyloxy) -1-methylcyclohexyl] amine hydrochloride (D60, 200 mg, 1.03 mmol) in a mixture of ethanol (12 ml) and water (6 ml) at room temperature under argon. Treatment with potassium (156 mg, 1.13 mmol) followed by 1-ethyl-1-methyl-4-oxopiperidinium iodide (D44, 404 mg, 1.50 mmol) followed by heating at 80 ° C. for 1.5 hours. The mixture was cooled and concentrated in vacuo to approximately 7 ml, then treated with NaHCO ₃ solution (15 ml) and extracted with dichloromethane (3 × 20 ml). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a brown oil (250 mg) that was chromatographed on silica gel eluting with 0-5% MeOH / dichloromethane to give the title compound. As a yellow oil (140 mg, 57%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.89 (3H, s), 1.13-1.27 (2H, m), 1.20 (3H, t), 1.68-1.80 (4H, m), 1.95-2.05 (2H, m), 2.40-2.47 (4H, m), 2.76-2.83 (4H, m), 3.25-3.33 (1H, m), 3.52 (2H, q)

（Ｄ６２）
２Ｍ ＮＨ_３／ＭｅＯＨ（１２ｍｌ）中、１−［シス−４−エトキシ−１−メチルシクロヘキシル］−４−ピペリジノン（Ｄ６１、１４０ｍｇ、０．５８５ｍｍｏｌ）の溶液を１０％Ｐｄ／Ｃペースト（３０ｍｇ）で処理し、初期気圧５０ｐｓｉの水素雰囲気下で２．５日間振盪した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過して触媒を除去し、濾液を真空濃縮し、標題化合物を無色の油状物として得た（１４０ｍｇ、１００％）。
¹H NMR δ(CDCl₃, 400 MHz): 0.84 (3H, s), 1.04-1.20 (2H, m), 1.20 (3H, t), 1.37-1.50 (2H, m), 1.58-1.72 (4H, m), 1.83-2.00 (4H, m), 2.05-2.20 (2H, m), 2.65-2.75 (1H, m), 2.88 (2H, br d), 3.20-3.30 (1H, m), 3.20-3.80 (3.50 = 2H, qを含む4Hと仮定) Description 62.1- [cis-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidineamine (D62)

(D62)
A solution of 1- [cis-4-ethoxy-1-methylcyclohexyl] -4-piperidinone (D61, 140 mg, 0.585 mmol) in 2M NH ₃ / MeOH (12 ml) with 10% Pd / C paste (30 mg). Treated and shaken under hydrogen atmosphere with initial pressure of 50 psi for 2.5 days. The mixture was filtered through Kieselguhr to remove the catalyst and the filtrate was concentrated in vacuo to give the title compound as a colorless oil (140 mg, 100%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.84 (3H, s), 1.04-1.20 (2H, m), 1.20 (3H, t), 1.37-1.50 (2H, m), 1.58-1.72 (4H, m), 1.83-2.00 (4H, m), 2.05-2.20 (2H, m), 2.65-2.75 (1H, m), 2.88 (2H, br d), 3.20-3.30 (1H, m), 3.20-3.80 (Assuming 3.50 = 2H, 4H including q)

（Ｄ６３）
アセトニトリル（３００ｍｌ）中、４−｛［（１，１−ジメチルエチル）（ジメチル）シリル］オキシ｝シクロヘキサンカルボン酸シス／トランスエチル（Ｄ５０、２５．２ｇ）、三臭化ビスマス（４．４ｇ）、トリエチルシラン（１７．５ｍｌ）の溶液に、アセトニトリル（５０ｍｌ）中、プロピオンアルデヒド（６．４ｇ）を３０分かけて加え、この混合物をさらに１．５時間攪拌した。溶媒を部分的に除去した後、残渣を酢酸エチルおよび飽和重炭酸ナトリウム溶液で処理した。有機層を分離し、ブラインで洗浄し、無水硫酸ナトリウムで乾燥させ、溶媒を除去し、シリコーン残渣が混入した標題化合物を得た（３９．１ｇ）。 Description 63 4- (propyloxy) cyclohexanecarboxylic acid cis / trans-ethyl (D63)

(D63)
4-{[(1,1-dimethylethyl) (dimethyl) silyl] oxy} cyclohexanecarboxylic acid cis / transethyl (D50, 25.2 g), bismuth tribromide (4.4 g) in acetonitrile (300 ml), To a solution of triethylsilane (17.5 ml) was added propionaldehyde (6.4 g) in acetonitrile (50 ml) over 30 minutes and the mixture was stirred for an additional 1.5 hours. After partial removal of the solvent, the residue was treated with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, the solvent was removed to give the title compound contaminated with silicone residue (39.1 g).

（Ｄ６４）
記載６３から得られた生成物（３９．１ｇ）、４０％ｗ／ｗ水酸化ナトリウム溶液（１５０ｍｌ）テトラヒドロフラン（２００ｍｌ）およびメタノール（１５０ｍｌ）をおよそ７２時間攪拌した。溶媒を部分的に除去した後、得られた混合物を酢酸エチルおよび水で処理した。水層を分離し、濃塩酸で酸性化し、ジエチルエーテルで抽出した。エーテル層をブラインで洗浄し、無水硫酸ナトリウムで乾燥させ、溶媒を除去し、標題化合物を油状物として得た（１５．４２ｇ）。 Description 64. Cis / trans-4- (propyloxy) cyclohexanecarboxylic acid (D64)

(D64)
The product obtained from description 63 (39.1 g), 40% w / w sodium hydroxide solution (150 ml) tetrahydrofuran (200 ml) and methanol (150 ml) were stirred for approximately 72 hours. After partial removal of the solvent, the resulting mixture was treated with ethyl acetate and water. The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The ether layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed to give the title compound as an oil (15.42g).

（Ｄ６５）
−２０℃にてアルゴン下、ＴＨＦ（３００ｍｌ）中、ジイソプロピルアミン（２４ｍｌ、０．１７ｍｏｌ）の攪拌溶液を、ヘキサン（６８ｍｌ、０．１７ｍｏｌ）中２．５Ｍのｎ−ブチルリチウムで１０分かけて処理した後、０℃まで温め、１５分間攪拌した。この混合物を再び−１０℃まで冷却し、ＴＨＦ中、４−（プロピルオキシ）シクロヘキサンカルボン酸（Ｄ６４、１３．８ｇ、０．０７４ｍｏｌ）の溶液で１０分かけて処理した。得られた黄色溶液を５０℃で２．５時間加熱した後、０℃まで冷却し、ヨードメタン（１３．８ｍｌ、０．２２ｍｏｌ）で処理した。この混合物を室温まで温め、２０時間攪拌したところ、黄色沈殿が生じた。この混合物を１０℃まで冷却し、１０％クエン酸溶液（２００ｍｌ）で処理した後、およそ２５０ｍｌ容量まで真空濃縮した。残った混合物を水（２００ｍｌ）で希釈し、Ｅｔ_２Ｏで抽出した（３×２５０ｍｌ）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮して黄色油状物を得（１５．０ｇ）、これはおよそシス：トランス異性体の６０：４０混合物であった。 Description 65. Cis / trans-1-methyl-4- (propyloxy) cyclohexanecarboxylic acid (D65)

(D65)
A stirred solution of diisopropylamine (24 ml, 0.17 mol) in THF (300 ml) under argon at −20 ° C. with 2.5 M n-butyllithium in hexane (68 ml, 0.17 mol) over 10 minutes. After treatment, warmed to 0 ° C. and stirred for 15 minutes. The mixture was again cooled to −10 ° C. and treated with a solution of 4- (propyloxy) cyclohexanecarboxylic acid (D64, 13.8 g, 0.074 mol) in THF over 10 minutes. The resulting yellow solution was heated at 50 ° C. for 2.5 hours, then cooled to 0 ° C. and treated with iodomethane (13.8 ml, 0.22 mol). The mixture was warmed to room temperature and stirred for 20 hours resulting in the formation of a yellow precipitate. The mixture was cooled to 10 ° C., treated with 10% citric acid solution (200 ml) and then concentrated in vacuo to approximately 250 ml volume. The remaining mixture was diluted with water (200 ml) and extracted with Et ₂ O (3 × 250 ml). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a yellow oil (15.0 g) which was approximately a 60:40 mixture of cis: trans isomers.

（Ｄ６６）
１０℃にて、攪拌した塩化チオニル（５０ｍｌ）、０．６８ｍｏｌ）に、シス／トランス−１−メチル−４−（プロピルオキシ）シクロヘキサンカルボン酸（Ｄ６５、１３ｇ、０．０７０ｍｏｌ）を加え、室温まで温めた後、８５℃で３時間加熱した。この混合物を真空濃縮し、残渣を、トルエンを用いて２回濃縮し、過剰な塩化チオニルを除去した。残渣をＴＨＦ（１００ｍｌ）に溶解し、希ＮａＨＣＯ_３溶液（２５０ｍｌ）で処理し、室温で２４時間よく攪拌した後、室温で３日間放置した。このとき、２ｇのシス／トランス−１−メチル−４−（プロピルオキシ）シクロヘキサンカルボン酸に対する同じ段階のより小規模な反応から得られた混合物を合わせた。合わせた混合物をおよそ３００ｍｌまで真空濃縮し、水性残渣をＥｔ_２Ｏで洗浄し（２×１２０ｍｌ）、その後、２Ｍ ＨＣｌで酸性化し、ＥｔＯＡｃで抽出した（２×１５０ｍｌ）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、標題化合物を淡黄色固体として得た（５．１ｇ、３４％）。
¹H NMR δ(CDCl₃, 400 MHz): 0.92 (3H, t), 1.24 (3H, s), 1.54-1.74 (8H, m), 1.78-1.88 (2H, m), 3.33-3.40 (3H, m) 1Hはスペクトルから識別できない。 Description 66. Trans-1-methyl-4- (propyloxy) cyclohexanecarboxylic acid (D66)

(D66)
Add cis / trans-1-methyl-4- (propyloxy) cyclohexanecarboxylic acid (D65, 13 g, 0.070 mol) to thionyl chloride (50 ml), 0.68 mol) stirred at 10 ° C. until room temperature. After warming, it was heated at 85 ° C. for 3 hours. The mixture was concentrated in vacuo and the residue was concentrated twice with toluene to remove excess thionyl chloride. The residue was dissolved in THF (100 ml), treated with dilute NaHCO ₃ solution (250 ml), stirred well at room temperature for 24 hours, and then allowed to stand at room temperature for 3 days. At this time, the mixtures resulting from a smaller reaction of the same stage on 2 g of cis / trans-1-methyl-4- (propyloxy) cyclohexanecarboxylic acid were combined. The combined mixture was concentrated in vacuo to approximately 300 ml and the aqueous residue was washed with Et ₂ O (2 × 120 ml) then acidified with 2M HCl and extracted with EtOAc (2 × 150 ml). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a pale yellow solid (5.1 g, 34%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.92 (3H, t), 1.24 (3H, s), 1.54-1.74 (8H, m), 1.78-1.88 (2H, m), 3.33-3.40 (3H, m) 1H cannot be distinguished from the spectrum.

（Ｄ６７）
室温にてアルゴン下、トルエン（１２０ｍｌ）中、トランス−１−メチル−４−（プロピルオキシ）シクロヘキサンカルボン酸（Ｄ６６、５．１ｇ、０．０２７ｍｏｌ）の攪拌溶液をトリエチルアミン（４．９ｍｌ、０．０３５ｍｏｌ）およびアジ化ジフェニルホスホリル（５．８ｍｌ、０．０２７ｍｏｌ）で処理し、８５℃で１時間加熱した。この混合物を室温まで冷却した後、１Ｍ ＮａＯＨ溶液（２００ｍｌ）で処理し、Ｅｔ_２Ｏで抽出した（２×１５０ｍｌ）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、標題化合物を黄色油状物として得た（５．０ｇ、１００％）。
¹H NMR δ(CDCl₃, 400 MHz): 0.91 (3H, t), 1.36 (3H, s), 1.50-1.60 (4H, m), 1.65-1.80 (6H, m), 3.33 (2H, t), 3.46-3.52 (1H, m) Description 67. Trans-1-isocyanato-1-methyl-4- (propyloxy) cyclohexane (D67)

(D67)
A stirred solution of trans-1-methyl-4- (propyloxy) cyclohexanecarboxylic acid (D66, 5.1 g, 0.027 mol) in toluene (120 ml) under argon at room temperature was triethylamine (4.9 ml, 0.0. 035 mol) and diphenylphosphoryl azide (5.8 ml, 0.027 mol) and heated at 85 ° C. for 1 hour. The mixture was cooled to room temperature and then treated with 1M NaOH solution (200 ml) and extracted with Et ₂ O (2 × 150 ml). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a yellow oil (5.0 g, 100%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.91 (3H, t), 1.36 (3H, s), 1.50-1.60 (4H, m), 1.65-1.80 (6H, m), 3.33 (2H, t) , 3.46-3.52 (1H, m)

（Ｄ６８）
ＴＨＦ（１００ｍｌ）中、トランス−１−イソシアナト−１−メチル−４−（プロピルオキシ）シクロヘキサン（Ｄ６７、５．０ｇ、０．０２７ｍｏｌ）の溶液を５Ｍ ＨＣｌ（２５ｍｌ）で処理し、室温にてアルゴン下で２０時間攪拌した後、真空濃縮し、残渣をトルエンと共沸させて水の痕跡を除去した。残った半固体をＥｔ_２Ｏ（１２０ｍｌ）でトリチュレートして固体を得、これを濾別し、Ｅｔ_２Ｏで洗浄し、真空下５０℃で乾燥させ、標題化合物を白色固体として得た（４．５ｇ、８５％）。
¹H NMR δ(CDCl₃, 400 MHz): 0.91 (3H, t), 1.47 (3H, s), 1-45-1.70 (4H, m), 1.75-2.00 (6H, m), 3.52 (2H, t), 3.40-3.48 (1H, m), 8.38 (3H, br s) Description 68. [Trans-1-methyl-4- (propyloxy) cyclohexyl] amine hydrochloride (D68)

(D68)
A solution of trans-1-isocyanato-1-methyl-4- (propyloxy) cyclohexane (D67, 5.0 g, 0.027 mol) in THF (100 ml) was treated with 5M HCl (25 ml) and argon at room temperature. After stirring for 20 hours under vacuum, it was concentrated in vacuo and the residue was azeotroped with toluene to remove traces of water. The remaining semi-solid was triturated with Et ₂ O (120 ml) to give a solid which was filtered off, washed with Et ₂ O and dried under vacuum at 50 ° C. to give the title compound as a white solid (4 .5g, 85%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.91 (3H, t), 1.47 (3H, s), 1-45-1.70 (4H, m), 1.75-2.00 (6H, m), 3.52 (2H, t), 3.40-3.48 (1H, m), 8.38 (3H, br s)

（Ｄ６９）
室温にてアルゴン下、エタノール（１００ｍｌ）と水（６０ｍｌ）の混合物中、［トランス−１−メチル−４−（プロピルオキシ）シクロヘキシル］アミン塩酸塩（Ｄ６８、４．５ｇ、０．０２２ｍｏｌ）の攪拌溶液を炭酸カリウム（３．３１ｇ、０．０２４ｍｏｌ）、次いで１−エチル−１−メチル−４−オキソピペリジニウムヨージド（Ｄ４４、８．９１ｇ、０．０３３ｍｏｌ）で処理した後、８０℃で２．５時間加熱した。この混合物を冷却し、およそ６０ｍｌまで真空濃縮した後、水性残渣を飽和ＮａＨＣＯ_３溶液で処理し、ＤＣＭ（３×８０ｍｌ）で抽出した。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮して橙色の油状物（６．１ｇ）を得、これを０〜１０％ＭｅＯＨ／ＤＣＭで溶出するシリカゲルでのクロマトグラフィーに付し、標題化合物を黄色油状物として得た（３．４５ｇ、６３％）。
¹H NMR δ(CDCl₃, 400 MHz): 0.93 (3H, s + 3H, t), 1.48-1.72 (8H, m), 1.80-1.92 (2H, m), 2.41 (4H, t), 2.82 (4H, t), 3.35-3.45 (3H, t + m) Description 69.1- [trans-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinone (D69)

(D69)
Stirring [trans-1-methyl-4- (propyloxy) cyclohexyl] amine hydrochloride (D68, 4.5 g, 0.022 mol) in a mixture of ethanol (100 ml) and water (60 ml) under argon at room temperature. The solution was treated with potassium carbonate (3.31 g, 0.024 mol) followed by 1-ethyl-1-methyl-4-oxopiperidinium iodide (D44, 8.91 g, 0.033 mol) and then at 80 ° C. Heated for 2.5 hours. After the mixture was cooled and concentrated in vacuo to approximately 60 ml, the aqueous residue was treated with saturated NaHCO ₃ solution and extracted with DCM (3 × 80 ml). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give an orange oil (6.1 g) which was chromatographed on silica gel eluting with 0-10% MeOH / DCM. The title compound was obtained as a yellow oil (3.45 g, 63%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.93 (3H, s + 3H, t), 1.48-1.72 (8H, m), 1.80-1.92 (2H, m), 2.41 (4H, t), 2.82 ( 4H, t), 3.35-3.45 (3H, t + m)

（Ｄ７０）
２Ｍ ＮＨ_３／ＭｅＯＨ（６０ｍｌ）中、１−［トランス−１−メチル−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジノン（Ｄ６９、２．０ｇ、０．００７９ｍｏｌ）の溶液を１０％Ｐｄ／Ｃ（１５０ｍｇ）で処理し、室温にて３．５日間、初期気圧５５ｐｓｉの水素雰囲気下で振盪した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過して触媒を除去し、濾液を真空濃縮し、標題化合物を白色固体として得た（１．８２ｇ、９１％）。
¹H NMR δ(CDCl₃, 400 MHz): 0.91 (3H, t), 1.08 (3H, br s), 1.32-1.45 (2H, m), 1.5-1-60 (2H, m), 1.62-2.60 (12H, ブロードシグナルのセットと仮定), 2.70-3.10 (1H, br), 34.10-3.25 (2H, br), 3.30-3.45 (3H, m), 3.40-4.40 (2H, v br) Description 70.1- [trans-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidineamine (D70)

(D70)
A solution of 1- [trans-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinone (D69, 2.0 g, 0.0079 mol) in 2M NH ₃ / MeOH (60 ml) was added to 10% Pd / C. (150 mg) and shaken at room temperature for 3.5 days in a hydrogen atmosphere with an initial pressure of 55 psi. The mixture was filtered through Kieselguhr to remove the catalyst and the filtrate was concentrated in vacuo to give the title compound as a white solid (1.82 g, 91%).
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.91 (3H, t), 1.08 (3H, br s), 1.32-1.45 (2H, m), 1.5-1-60 (2H, m), 1.62-2.60 (Assuming 12H, broad signal set), 2.70-3.10 (1H, br), 34.10-3.25 (2H, br), 3.30-3.45 (3H, m), 3.40-4.40 (2H, v br)

（Ｄ７１）
室温にてアルゴン下、ＤＭＦ（３ｍｌ）中、２，４−ジフルオロ−１−ニトロベンゼン（１００ｍｇ、０．６３ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（０．４０ｍｌ、２．２ｍｍｏｌ）、次いで１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ１２、１７９ｍｇ、０．６０ｍｍｏｌ）で処理した後、室温で２０時間維持し、その後、５０℃で７時間加熱した。この混合物を真空濃縮し、残渣を１０％Ｎａ_２ＣＯ_３溶液（１０ｍｌ）で処理し、ジクロロメタンで抽出した（２×１５ｍｌ）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ４）、真空濃縮し、残渣を０〜１０％メタノール／ジクロロメタンで溶出するシリカゲル（１０ｇ）でのクロマトグラフィーに付して黄色固体を得、これをメタノールから再結晶させ、標題化合物を黄色固体として得た（１２０ｍｇ、５５％）。ＭＨ^＋３６６
¹H NMR δ(CDCl₃, 400 MHz): 1.15-1.40 (7H, m), 1.60-1.72 (2H, m), 1.90-1.96 (2H, m), 2.05-2.18 (4H, m), 2.30-2.50 (3H, m), 2.85-2.93 (2H, m), 3.13-3.23 (1H, m), 3.38-3.50 (1H, m), 3.52 (2H, q), 6.31-6.40 (1H, m), 6.48 (1H, dd), 8.18-8.30 (2H, m) Description 71.1- [trans-4- (ethyloxy) cyclohexyl] -N- (5-fluoro-2-nitrophenyl) -4-piperidineamine (D71)

(D71)
A stirred solution of 2,4-difluoro-1-nitrobenzene (100 mg, 0.63 mmol) in DMF (3 ml) under argon at room temperature was diluted with diisopropylethylamine (0.40 ml, 2.2 mmol) and then 1- [trans- After treatment with 4- (ethyloxy) cyclohexyl] -4-piperidineamine dihydrochloride (D12, 179 mg, 0.60 mmol), it was maintained at room temperature for 20 hours and then heated at 50 ° C. for 7 hours. The mixture was concentrated in vacuo and the residue was treated with 10% Na ₂ CO ₃ solution (10 ml) and extracted with dichloromethane (2 × 15 ml). The combined extracts were dried (Na ₂ SO 4), concentrated in vacuo, and the residue was chromatographed on silica gel (10 g) eluting with 0-10% methanol / dichloromethane to give a yellow solid that was extracted from methanol. Recrystallization gave the title compound as a yellow solid (120 mg, 55%). MH ⁺ 366
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.15-1.40 (7H, m), 1.60-1.72 (2H, m), 1.90-1.96 (2H, m), 2.05-2.18 (4H, m), 2.30- 2.50 (3H, m), 2.85-2.93 (2H, m), 3.13-3.23 (1H, m), 3.38-3.50 (1H, m), 3.52 (2H, q), 6.31-6.40 (1H, m), 6.48 (1H, dd), 8.18-8.30 (2H, m)

（Ｄ７２）
室温にてアルゴン下、エタノール（１５ｍｌ）中、１−［トランス−４−（エチルオキシ）シクロヘキシル］−Ｎ−（５−フルオロ−２−ニトロフェニル）−４−ピペリジンアミン（Ｄ７１、１２０ｍｇ、０．３３ｍｍｏｌ）の攪拌溶液をラネーニッケル（〜２０ｍｇ）、次いでヒドラジン水和物（０．１０ｍｌ、３．３ｍｍｏｌ）で処理し、２時間維持した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過して触媒を除去し、濾液を真空濃縮し、標題化合物を淡褐色固体として得た（１１０ｍｇ、収率１００％）。ＭＨ^＋ ３３６
¹H NMR δ(CDCl₃, 400MHz): 1.17-1.37 (4H, m), 1.20 (3H, t), 1.42-1.54 (2H, m), 1.88-1.96 (2H, m), 2.02-2.15 (4H, m), 2.28-2.42 (3H, m), 2.92 (2H, br d), 3.07 (2H, br s), 3.13-3.25 (2H, m), 3.51 (2H, q), 3.60 (1H, br s), 6.25-6.40 (2H, m), 6.60-6.67 (1H, m) Description 72. N ² - {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -4-fluoro-1,2-benzenediamine (D72)

(D72)
1- [trans-4- (ethyloxy) cyclohexyl] -N- (5-fluoro-2-nitrophenyl) -4-piperidinamine (D71, 120 mg, 0.33 mmol) in ethanol (15 ml) under argon at room temperature. ) Was treated with Raney nickel (˜20 mg) followed by hydrazine hydrate (0.10 ml, 3.3 mmol) and maintained for 2 hours. The mixture was filtered through Kieselguhr to remove the catalyst and the filtrate was concentrated in vacuo to give the title compound as a light brown solid (110 mg, 100% yield). MH ⁺ 336
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.17-1.37 (4H, m), 1.20 (3H, t), 1.42-1.54 (2H, m), 1.88-1.96 (2H, m), 2.02-2.15 (4H , m), 2.28-2.42 (3H, m), 2.92 (2H, br d), 3.07 (2H, br s), 3.13-3.25 (2H, m), 3.51 (2H, q), 3.60 (1H, br s), 6.25-6.40 (2H, m), 6.60-6.67 (1H, m)

（Ｄ７３）
ジメチルホルムアミド（２０ｍｌ）中、４−ブロモ−２−フルオロ−１−ニトロベンゼン（６００ｍｇ、２．７２ｍｍｏｌ）および１−［トランス−４−（エトキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ１２、８０７ｍｇ、２．７２ｍｍｏｌ）の混合物をジイソプロピルエチルアミン（１．４ｍｌ、８．１６ｍｍｏｌ）で処理した後、８０℃にてアルゴン下で一晩、攪拌しながら加熱した。この溶液を水で洗浄した後、ジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、濃縮した。残渣をＳＣＸカートリッジに乗せ、まずジクロロメタン（およそ３０ｍｌ）で、次いで２Ｍ ＮＨ_３／ＭｅＯＨ（およそ３０ｍｌ）で溶出した。このメタノール溶液を真空濃縮し、黄色／橙色固体を得た（１．４ｇ）。これを３〜２５％ＥｔＯＡｃ／ヘキサンで溶出するアミノシリカカラム（４０＋Ｍ）でのクロマトグラフィーにより精製し、標題化合物を得た（１．１５ｇ、９９％）。ＭＨ＋＝４２７、４２８
¹H NMR δ(CDCl₃, 400MHz): 1.15-1.38 (4H, m), 1.20 (3H, t), 1.58-1.72 (2H, m), 1.88-1.98 (2H, m), 2.02-2.16 (4H, m), 2.3-2.38 (1H, m), 2.402.50 (2H, m), 2.85-2.95 (2H, m), 3.13-3.24 (1H, m), 3.50 (2H, t), 6.73 (1H, dd), 7.00 (1H, d), 8.03 (1H, d), 8.14 (1H, d) Description 73. N- (5-bromo-2-nitrophenyl) -1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinamine (D73)

(D73)
4-Bromo-2-fluoro-1-nitrobenzene (600 mg, 2.72 mmol) and 1- [trans-4- (ethoxy) cyclohexyl] -4-piperidineamine dihydrochloride (D12, 807 mg) in dimethylformamide (20 ml). (2.72 mmol) was treated with diisopropylethylamine (1.4 ml, 8.16 mmol) and then heated at 80 ° C. under argon overnight with stirring. The solution was washed with water and extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ) and concentrated. The residue was loaded onto an SCX cartridge and eluted first with dichloromethane (approximately 30 ml) and then with 2M NH ₃ / MeOH (approximately 30 ml). The methanol solution was concentrated in vacuo to give a yellow / orange solid (1.4 g). This was purified by chromatography on an amino silica column (40 + M) eluting with 3-25% EtOAc / hexanes to give the title compound (1.15 g, 99%). MH + = 427, 428
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.15-1.38 (4H, m), 1.20 (3H, t), 1.58-1.72 (2H, m), 1.88-1.98 (2H, m), 2.02-2.16 (4H , m), 2.3-2.38 (1H, m), 2.402.50 (2H, m), 2.85-2.95 (2H, m), 3.13-3.24 (1H, m), 3.50 (2H, t), 6.73 (1H , dd), 7.00 (1H, d), 8.03 (1H, d), 8.14 (1H, d)

（Ｄ７４）
室温にてアルゴン下、エタノール（１００ｍｌ）中、Ｎ−（５−ブロモ−２−ニトロフェニル）−１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ７３、６５０ｍｇ、１．５３ｍｍｏｌ）の攪拌溶液をラネーニッケル（１００ｍｇ）で処理し、ヒドラジン水和物（１．２ｍｌ、３８．２５ｍｍｏｌ）を滴下し、３時間維持した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過し、濾液を真空濃縮し、標題化合物を琥珀色の油状物として得た（６００ｍｇ、９９％）。ＭＨ＋＝３９７、３９８
¹H NMR δ(CDCl₃, 400MHz): 1.20 (3H, t), 1.20-1.40 (4H, m), 1.38-1.55 (2H, m), 1.90-2.00 (2H, m), 2.00-2.15 (4H, m), 2.25-2.43 (3H, m), 2.90 (2H, br d), 3.13-3.43 (5H, m), 3.51 (2H, t), 6.57 (1H, d), 6.70-6.78 (2H, m) Wherein 74.4- Bromo ^-N 2 - {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D74)

(D74)
N- (5-bromo-2-nitrophenyl) -1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidineamine (D73, 650 mg, 1.53 mmol) in ethanol (100 ml) under argon at room temperature. ) Was treated with Raney nickel (100 mg) and hydrazine hydrate (1.2 ml, 38.25 mmol) was added dropwise and maintained for 3 hours. The mixture was filtered through Kieselguhr and the filtrate was concentrated in vacuo to give the title compound as an amber oil (600 mg, 99%). MH + = 397, 398
¹ H NMR δ (CDCl ₃ , 400MHz): 1.20 (3H, t), 1.20-1.40 (4H, m), 1.38-1.55 (2H, m), 1.90-2.00 (2H, m), 2.00-2.15 (4H , m), 2.25-2.43 (3H, m), 2.90 (2H, br d), 3.13-3.43 (5H, m), 3.51 (2H, t), 6.57 (1H, d), 6.70-6.78 (2H, m)

（Ｄ７５）
室温にてアルゴン下、トルエン（１５ｍｌ）中、Ｎ−（５−ブロモ−２−ニトロフェニル）−１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ７３、５００ｍｇ、１．１７ｍｍｏｌ）およびトリブチルビニルスズ（０．４２ｍｌ、１．３６ｍｍｏｌ）の溶液をトリフェニルホスフィン（７７ｍｇ、０．２９ｍｍｏｌ）およびビス（ジベンジリデン）アセトン）パラジウム（０）（１０２ｍｇ、０．１８ｍｍｏｌ）で処理し、１２０℃で一晩加熱した。この混合物を冷却した後、Ｋｉｅｓｅｌｇｕｈｒで濾過した。この有機濾液を１０％水酸化アンモニウム水溶液および水で洗浄した後、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、褐色固体（およそ５５０ｍｇ）を得た。これをジクロロメタンに溶解し、ＳＣＸカートリッジで溶離させた後、２Ｍ ＮＨ_３／ＭｅＯＨで溶出することにより回収し、濃縮した。残渣を４０＋Ｍ Ｂｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカカラムにてクロマトグラフィーに付し、標題化合物を橙色固体として得た（９９％）。ＭＨ＋＝３７４
¹H NMR δ(CDCl₃, 400MHz): 1.18-1.40 (4H, m), 1.20 (3H, t), 1.55-1.73 (2H, mと仮定), 1.90-2.00 (2H, m), 2.03-2.18 (4H, m), 2.30-2.40 (1H, m), 2.40-2.50 (2H, m), 2.85-2.94 (2H, m), 3.13-3.23 (1H, m), 3.50-3.61 (1H, m), 3.51 (2H, q), 5.46 (1H, d), 5.87 (1H, d), 6.66 (1H, dd), 6.72 (2H, m), 8.14 (1H, dd), 8.22 (1H, d) Description 75. N- (5-ethenyl-2-nitrophenyl) -1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidineamine (D75)

(D75)
N- (5-Bromo-2-nitrophenyl) -1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinamine (D73, 500 mg, 1.17 mmol) in toluene (15 ml) under argon at room temperature. ) And tributylvinyltin (0.42 ml, 1.36 mmol) are treated with triphenylphosphine (77 mg, 0.29 mmol) and bis (dibenzylidene) acetone) palladium (0) (102 mg, 0.18 mmol); Heated at 120 ° C. overnight. The mixture was cooled and then filtered through Kieselguhr. The organic filtrate was washed with 10% aqueous ammonium hydroxide and water, then dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a brown solid (approximately 550 mg). This was dissolved in dichloromethane, eluted with an SCX cartridge, then collected by eluting with 2M NH ₃ / MeOH and concentrated. The residue was chromatographed on a 40 + M Biotage KP-NH ™ -silica column to give the title compound as an orange solid (99%). MH + = 374
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.18-1.40 (4H, m), 1.20 (3H, t), 1.55-1.73 (assuming 2H, m), 1.90-2.00 (2H, m), 2.03-2.18 (4H, m), 2.30-2.40 (1H, m), 2.40-2.50 (2H, m), 2.85-2.94 (2H, m), 3.13-3.23 (1H, m), 3.50-3.61 (1H, m) , 3.51 (2H, q), 5.46 (1H, d), 5.87 (1H, d), 6.66 (1H, dd), 6.72 (2H, m), 8.14 (1H, dd), 8.22 (1H, d)

（Ｄ７６）
室温にてアルゴン下、１０分間、メタノール（５０ｍｌ）中、Ｎ−（５−エテニル−２−ニトロフェニル）−１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ７５、４４０ｍｇ、１．１７ｍｍｏｌ）およびギ酸アンモニウム（７３４ｍｇ、１１．７ｍｍｏｌ）の混合物を攪拌した後、１０％Ｐｄ／Ｃ（２６１ｍｇ、０．２当量）で処理し、３０分間攪拌した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過し、濃縮して溶媒を除去した。残渣をジクロロメタンに溶解し、２Ｍ ＮａＯＨ溶液で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、濃縮標題化合物を紫色の粘稠な油状物として得た（３４８ｍｇ、８６％）。ＭＨ＋＝３４６
¹H NMR δ(CDCl₃, 400MHz): 1.18-1.40 (10H, t + t + m), 1.42-1.58 (2H, m), 1.90-2.00 (2H, m), 2.03-2.16 (4H, m), 2.30-2.42 (3H, m), 2.53 (2H, q), 2.86-2.95 (2H, m), 3.00-3.40 (5H, mと仮定), 3.51 (2H, q), 6.50 (2H, m), 6.65 (1H, d) Wherein 76.4- ethyl ^-N 2 - {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D76)

(D76)
N- (5-ethenyl-2-nitrophenyl) -1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidineamine (D75, 440 mg, in methanol (50 ml) at room temperature under argon for 10 min. 1.17 mmol) and ammonium formate (734 mg, 11.7 mmol) were stirred and then treated with 10% Pd / C (261 mg, 0.2 eq) and stirred for 30 minutes. The mixture was filtered through Kieselguhr and concentrated to remove the solvent. The residue was dissolved in dichloromethane, washed with 2M NaOH solution and dried (Na ₂ SO ₄ ) to give the concentrated title compound as a purple viscous oil (348 mg, 86%). MH + = 346
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.18-1.40 (10H, t + t + m), 1.42-1.58 (2H, m), 1.90-2.00 (2H, m), 2.03-2.16 (4H, m) , 2.30-2.42 (3H, m), 2.53 (2H, q), 2.86-2.95 (2H, m), 3.00-3.40 (assuming 5H, m), 3.51 (2H, q), 6.50 (2H, m) , 6.65 (1H, d)

（Ｄ７７）
ジメチルホルムアミド（２０ｍｌ）中、４−シクロプロピル−２−フルオロ−１−ニトロベンゼン（２００ｍｇ、１．１ｍｍｏｌ）および１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ１２、３２７ｍｇ、１．１ｍｍｏｌ）の混合物をジイソプロピルエチルアミン（０．５６ｍｌ）で処理した後、アルゴン下で８０℃にて一晩加熱した。この溶液を水で洗浄した後、ジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残渣をジクロロメタンに溶解し、ＳＣＸカートリッジを通し、まずジクロロメタン、次いで２Ｍ ＮＨ_３／ＭｅＯＨで溶出した。このメタノール溶液を真空濃縮して暗橙色固体（３００ｍｇ）を得、これを５〜３０％ＥｔＯＡｃ／ヘキサンで溶出する４０＋Ｍ Ｂｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカカラムでのクロマトグラフィーにより精製し、標題化合物を橙色固体として得た（２４０ｍｇ、６０％）。ＭＨ＋＝３８８
¹H NMR δ(CDCl₃, 400MHz): 0.77-0.83 (2H, m), 1.03-1.11 (2H, m), 1.17-1.40 (4H, m), 1.20 (3H, t), 1.58-1.72 (2H, m), 1.82-1.98 (3H, m), 2.02-2.15 (4H, m), 2.30-2.40 (1H, m), 2.40-2.50 (2H, m), 2.82-2.92 (2H, m), 3.13-3.24 (1H, m), 3.48-3.62 (3H, t + m), 6.18 (1H, dd), 6.55 (1H, d), 8.05 (1H, d), 8.21 (1H, d) Description 77. N- (5-cyclopropyl-2-nitrophenyl) -1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidineamine (D77)

(D77)
4-Cyclopropyl-2-fluoro-1-nitrobenzene (200 mg, 1.1 mmol) and 1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidineamine dihydrochloride (D12, in dimethylformamide (20 ml) A mixture of 327 mg, 1.1 mmol) was treated with diisopropylethylamine (0.56 ml) and then heated at 80 ° C. overnight under argon. The solution was washed with water and extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dissolved in dichloromethane and passed through a SCX cartridge, eluting first with dichloromethane and then with 2M NH ₃ / MeOH. The methanol solution was concentrated in vacuo to give a dark orange solid (300 mg) which was purified by chromatography on a 40 + M Biotage KP-NH ™ -silica column eluting with 5-30% EtOAc / hexane to give the title compound Was obtained as an orange solid (240 mg, 60%). MH + = 388
¹ H NMR δ (CDCl ₃ , 400MHz): 0.77-0.83 (2H, m), 1.03-1.11 (2H, m), 1.17-1.40 (4H, m), 1.20 (3H, t), 1.58-1.72 (2H , m), 1.82-1.98 (3H, m), 2.02-2.15 (4H, m), 2.30-2.40 (1H, m), 2.40-2.50 (2H, m), 2.82-2.92 (2H, m), 3.13 -3.24 (1H, m), 3.48-3.62 (3H, t + m), 6.18 (1H, dd), 6.55 (1H, d), 8.05 (1H, d), 8.21 (1H, d)

（Ｄ７８）
室温にてアルゴン下、エタノール（４０ｍｌ）中、Ｎ−（５−シクロプロピル−２−ニトロフェニル）−１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ７７、２４０ｍｇ、０．６２ｍｍｏｌ）の攪拌溶液をラネーニッケル（５０ｍｇ）で処理し、ヒドラジン水和物（０．５ｍｌ、１５．５ｍｍｏｌ）を滴下し、２時間維持した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過し、濾液を真空濃縮し、標題化合物を緑色／黄色油状物として得た（２００ｍｇ、９０％）。ＭＨ＋＝３５８
¹H NMR δ(CDCl₃, 400MHz): 0.57-0.63 (2H, m), 0.83-0.90 (2H, m), 1.14-1.40 (4H, m), 1.20 (3H, t), 1.40-1.60 (2H, mと仮定), 1.75-1.85 (1H, m), 1.90-2.00 (2H, m), 2.02-2.16 (4H, m), 2.29-2.42 (3H, m), 2.87-2.93 (2H, m), 3.00-3.40 (5H, m), 3.45-3.57 (2H, q), 6.37 (1H, dd), 6.42 (1H, d), 6.62 (1H, d) Wherein 78.4- cyclopropyl ^-N 2 - {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D78)

(D78)
N- (5-Cyclopropyl-2-nitrophenyl) -1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinamine (D77, 240 mg, 0.4 mg) in ethanol (40 ml) under argon at room temperature. 62 mmol) was treated with Raney nickel (50 mg) and hydrazine hydrate (0.5 ml, 15.5 mmol) was added dropwise and maintained for 2 hours. The mixture was filtered through Kieselguhr and the filtrate was concentrated in vacuo to give the title compound as a green / yellow oil (200 mg, 90%). MH + = 358
¹ H NMR δ (CDCl ₃ , 400MHz): 0.57-0.63 (2H, m), 0.83-0.90 (2H, m), 1.14-1.40 (4H, m), 1.20 (3H, t), 1.40-1.60 (2H , m), 1.75-1.85 (1H, m), 1.90-2.00 (2H, m), 2.02-2.16 (4H, m), 2.29-2.42 (3H, m), 2.87-2.93 (2H, m) , 3.00-3.40 (5H, m), 3.45-3.57 (2H, q), 6.37 (1H, dd), 6.42 (1H, d), 6.62 (1H, d)

（Ｄ７９）
室温にてアルゴン下、ジメチルホルムアミド（４ｍｌ）中、３−フルオロ−４−ニトロアニソール（１２０ｍｇ、０．７０ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（０．４３ｍｌ、２．４ｍｍｏｌ）、次いで１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ１２、２００ｍｇ、０．６７ｍｍｏｌ）で処理し、５０℃で８時間、次いで９０℃で２０時間加熱した。この混合物を真空濃縮し、残渣を１０％Ｎａ_２ＣＯ_３溶液（１０ｍｌ）で処理し、ジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、残渣を０〜１０％メタノール／ジクロロメタンで溶出するシリカゲル（５ｇ）でのクロマトグラフィーに付して黄色油状物を得、これをメタノール（６ｍｌ）から結晶化させ、標題化合物を黄色固体として得た（１３０ｍｇ、５２％）。ＭＨ^＋ ３７８
¹H NMR δ(CDCl₃, 400 MHz): 1.15-1.38 (4H, m), 1.20 (3H, t), 1.6-1.75 (2H, m), 1.90-1.96 (2H, m), 2.02-2.15 (4H, m), 2.25-2.38 (1H, m), 2.38-2.48 (2H, m), 2.82-2.92 (2H, m), 3.12-3.23 (1H, m), 3.43-3.56 (3H, m), 3.86 (3H, s), 6.16 (1H, d), 6.2 (1H, dd), 8.15 (1H, d), 8.37 (1H, d) Description 79.1- [trans-4- (ethyloxy) cyclohexyl] -N- [5- (methyloxy) -2-nitrophenyl] -4-piperidinamine (D79)

(D79)
A stirred solution of 3-fluoro-4-nitroanisole (120 mg, 0.70 mmol) in dimethylformamide (4 ml) under argon at room temperature was diluted with diisopropylethylamine (0.43 ml, 2.4 mmol), then 1- [trans- Treated with 4- (ethyloxy) cyclohexyl] -4-piperidineamine dihydrochloride (D12, 200 mg, 0.67 mmol) and heated at 50 ° C. for 8 hours and then at 90 ° C. for 20 hours. The mixture was concentrated in vacuo and the residue was treated with 10% Na ₂ CO ₃ solution (10 ml) and extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ), concentrated in vacuo, and the residue was chromatographed on silica gel (5 g) eluting with 0-10% methanol / dichloromethane to give a yellow oil which was methanol ( From 6 ml) to give the title compound as a yellow solid (130 mg, 52%). MH ⁺ 378
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.15-1.38 (4H, m), 1.20 (3H, t), 1.6-1.75 (2H, m), 1.90-1.96 (2H, m), 2.02-2.15 ( 4H, m), 2.25-2.38 (1H, m), 2.38-2.48 (2H, m), 2.82-2.92 (2H, m), 3.12-3.23 (1H, m), 3.43-3.56 (3H, m), 3.86 (3H, s), 6.16 (1H, d), 6.2 (1H, dd), 8.15 (1H, d), 8.37 (1H, d)

（Ｄ８０）
室温にてアルゴン下、エタノール（１５ｍｌ）中、１−［トランス−４−（エチルオキシ）シクロヘキシル］−Ｎ−［５−（メチルオキシ）−２−ニトロフェニル］−４−ピペリジンアミン（Ｄ７９、１３０ｍｇ、０．３４ｍｍｏｌ）の攪拌溶液をラネーニッケル（〜２０ｍｇ）、次いでヒドラジン水和物（０．１０ｍｌ、３．３ｍｍｏｌ）で処理し、２時間維持した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過して触媒を除去し、濾液を真空濃縮し、標題化合物をベージュ色の固体として得た（１２０ｍｇ、収率１００％）。ＭＨ^＋３４８
¹H NMR δ(CDCl₃, 400MHz): 1.15-1.38 (4H, m), 1.18 (3H, t), 1.40-1.55 (2H, m), 1.90-1.96 (2H, m), 2.03-2.13 (4H, m), 2.23-2.38 (3H, m), 2.85-3.10 (4H, m), 3.13-3.26 (2H, m), 3.51 (2H, q), 3.60 (1H, br s), 3.75 (3H, s), 6.15 (1H, dd), 6.25 (1H, d), 6.65 (1H, d) Description 80. N ² - {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -4- (methyloxy) -1,2-benzenediamine (D80)

(D80)
1- [trans-4- (ethyloxy) cyclohexyl] -N- [5- (methyloxy) -2-nitrophenyl] -4-piperidineamine (D79, 130 mg, in ethanol (15 ml) under argon at room temperature. A stirred solution of 0.34 mmol) was treated with Raney nickel (˜20 mg) followed by hydrazine hydrate (0.10 ml, 3.3 mmol) and maintained for 2 hours. The mixture was filtered through Kieselguhr to remove the catalyst and the filtrate was concentrated in vacuo to give the title compound as a beige solid (120 mg, 100% yield). MH ⁺ 348
¹ H NMR δ (CDCl ₃ , 400MHz): 1.15-1.38 (4H, m), 1.18 (3H, t), 1.40-1.55 (2H, m), 1.90-1.96 (2H, m), 2.03-2.13 (4H , m), 2.23-2.38 (3H, m), 2.85-3.10 (4H, m), 3.13-3.26 (2H, m), 3.51 (2H, q), 3.60 (1H, br s), 3.75 (3H, s), 6.15 (1H, dd), 6.25 (1H, d), 6.65 (1H, d)

（Ｄ８１）
１，４−ジオキサン（３０ｍＬ）中、２−ブロモ−４−（トリフルオロメチルオキシ）アニリン（５．１ｇ）の溶液をビス（トリクロロメチル）カーボネート（２．２ｇ）で処理した。この混合物を１００℃まで加熱して透明な溶液を得た後、周囲温度まで冷却した。溶媒を蒸発させ、残渣をジクロロメタン（７０ｍｌ）に溶解し、４−アミノ−１−ピペリジンカルボン酸１，１−ジメチルエチル（４．０ｇ）を加えた。この混合物を一晩室温で攪拌した。シリカゲルを加え、溶媒を蒸発させた。残渣をシリカゲルクロマトグラフィーカラムに乗せ、ヘキサン／酢酸エチル０〜１００％で溶出し、次いで、ジクロロメタン／メタノール０〜１０％で溶出するシリカゲルでのクロマトグラフィーにより、ジエチルエーテルから標題化合物を白色固体として得た（４．３ｇ）。
¹HNMR δ(DMSO, 400 MHz): 1.25 (2H, m), 1.40 (9H, s), 1.79 (2H, m), 2.93 (2H, ブロード), 3.64 (1H, m), 3.80 (2H, m), 7.21 (1H, d), 7.35 (1H, d), 7.66 (1H, s), 7.91 (1H, s), 8.19 (1H, d) Description 81.4-{[({2-Bromo-4-[(trifluoromethyl) oxy] phenyl} amino) carbonyl] amino} -1-piperidinecarboxylic acid 1,1-dimethylethyl (D81)

(D81)
A solution of 2-bromo-4- (trifluoromethyloxy) aniline (5.1 g) in 1,4-dioxane (30 mL) was treated with bis (trichloromethyl) carbonate (2.2 g). The mixture was heated to 100 ° C. to obtain a clear solution and then cooled to ambient temperature. The solvent was evaporated and the residue was dissolved in dichloromethane (70 ml) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (4.0 g) was added. The mixture was stirred overnight at room temperature. Silica gel was added and the solvent was evaporated. Place the residue on a silica gel chromatography column, eluting with 0-100% hexane / ethyl acetate, then chromatography on silica gel eluting with dichloromethane / methanol 0-10% to give the title compound as a white solid from diethyl ether. (4.3 g).
¹ HNMR δ (DMSO, 400 MHz): 1.25 (2H, m), 1.40 (9H, s), 1.79 (2H, m), 2.93 (2H, broad), 3.64 (1H, m), 3.80 (2H, m ), 7.21 (1H, d), 7.35 (1H, d), 7.66 (1H, s), 7.91 (1H, s), 8.19 (1H, d)

（Ｄ８２）
１，４−ジオキサン（２０ｍＬ）中、トリス（ジベンジリデンアセトン）二パラジウム（０）（０．３３ｇ）、１，１’−ビス（ジフェニルホスフィノ）フェロセン（０．２１ｇ）、ナトリウムｔｅｒｔ−ブトキシド（１．１ｇ）の溶液をアルゴン雰囲気下で１０分間攪拌した。４−｛［（｛２−ブロモ−４−［（トリフルオロメチル）オキシ］フェニル｝アミノ）カルボニル］アミノ｝−１−ピペリジンカルボン酸１，１−ジメチルエチル（Ｄ８１、２．７ｇ）を加え、この混合物を９０℃まで加熱した。この混合物をこの温度で一晩攪拌した。この混合物をジクロロメタンに注ぎ、これを希塩化アンモニウム、ブラインで洗浄し、硫酸ナトリウムで乾燥させた。溶媒を除去し、残渣を酢酸エチル／ヘキサン０〜５０％で溶出するシリカゲルでのクロマトグラフィーに付し、標題化合物を固体泡沫として得た（１．５４ｇ）。
¹HNMR δ(DMSO, 400 MHz): 1.41 (9H, m), 1.72 (2H, s), 2.24 (2H, m), 2.85 (2H, ブロード), 4.18 (2H, m), 4.31 (1H, m), 6.88 (1H, d), 7.00 (1H, d), 7.10 (1H, s) Description 82.4- {2-Oxo-6-[(trifluoromethyl) oxy] -2,3-dihydro-1H-benzimidazol-1-yl} -1-piperidinecarboxylic acid 1,1-dimethylethyl (D82) )

(D82)
Tris (dibenzylideneacetone) dipalladium (0) (0.33 g), 1,1′-bis (diphenylphosphino) ferrocene (0.21 g), sodium tert-butoxide in 1,4-dioxane (20 mL) 1.1 g) was stirred for 10 minutes under an argon atmosphere. 4-{[({2-Bromo-4-[(trifluoromethyl) oxy] phenyl} amino) carbonyl] amino} -1-piperidinecarboxylic acid 1,1-dimethylethyl (D81, 2.7 g) was added; The mixture was heated to 90 ° C. The mixture was stirred at this temperature overnight. The mixture was poured into dichloromethane, which was washed with dilute ammonium chloride, brine and dried over sodium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane 0-50% to give the title compound as a solid foam (1.54 g).
¹ HNMR δ (DMSO, 400 MHz): 1.41 (9H, m), 1.72 (2H, s), 2.24 (2H, m), 2.85 (2H, broad), 4.18 (2H, m), 4.31 (1H, m ), 6.88 (1H, d), 7.00 (1H, d), 7.10 (1H, s)

（Ｄ８３）
メタノール（２０ｍｌ）中、４−｛２−オキソ−６−［（トリフルオロメチル）オキシ］−２，３−ジヒドロ−１Ｈ−ベンズイミダゾール−１−イル｝−１−ピペリジンカルボン酸１，１−ジメチルエチル（Ｄ８２、１．５４ｇ）の溶液を、エタノール（１０ｍｌ）中、塩化水素の飽和溶液で処理した。この混合物を１時間攪拌したところで溶媒を除去し、標題化合物を白色固体として得た（１．２８ｇ）。
¹HNMR δ(DMSO, 400 MHz): 1.81 (2H, m), 2.56 (2H, m), 3.04 (2H, m), 3.40 (2H, m), 4.56 (1H, m), 6.99 (1H, m), 7.05 (1H, d), 7.50 (1H, d), 8.97 (2H, br s), 11.2 (1H, s) Description 83.1- (4-Piperidinyl) -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D83)

(D83)
1,1-dimethyl 4- {2-oxo-6-[(trifluoromethyl) oxy] -2,3-dihydro-1H-benzimidazol-1-yl} -1-piperidinecarboxylate in methanol (20 ml) A solution of ethyl (D82, 1.54 g) was treated with a saturated solution of hydrogen chloride in ethanol (10 ml). The mixture was stirred for 1 hour and the solvent was removed to give the title compound as a white solid (1.28 g).
¹ HNMR δ (DMSO, 400 MHz): 1.81 (2H, m), 2.56 (2H, m), 3.04 (2H, m), 3.40 (2H, m), 4.56 (1H, m), 6.99 (1H, m ), 7.05 (1H, d), 7.50 (1H, d), 8.97 (2H, br s), 11.2 (1H, s)

（Ｄ８４）
０℃にて、ＴＨＦ（１１０ｍｌ）中、１，４−ジオキサスピロ［４，５］デカン−８−オール（Ｄ１、８，７ｇ、５５ｍｍｏｌ）の攪拌溶液を水素化ナトリウム（６０％を２．７ｇ、６６ｍｍｏｌ）で少量ずつ処理した。この混合物を室温で１時間攪拌した後、０℃まで冷却し、二硫化炭素（７ｍｌ、１１０ｍｍｏｌ）で滴下処理した。得られた混合物を室温で３時間攪拌した後、０℃まで冷却し、ヨードメタン（４．１２ｍｌ、６６ｍｍｏｌ）を滴下した。得られた混合物を１時間室温で攪拌した後、ＮＨ_４Ｃｌ水溶液で処理し、Ｅｔ_２Ｏで抽出した。有機相を分離し、水層をＥｔ_２Ｏで２回抽出した。合わせた有機液を、硫化水素ナトリウムを少量含む飽和ＮａＣｌ溶液で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、標題化合物を黄色／橙色油状物（定量的）として得た。
1H NMR (CDCl3, 400MHz): 1.62-1.72 (2H, m), 1.78-1.92 (2H, m), 1.95-2.06 (4H, m), 2.55 (3H, s), 3.92-4.02 (4H, m), 5.64-5.74 (1H, m) Description 84. S-methyldithiocarboxylic acid O-1,4-dioxaspiro [4.5] dec-8-yl (D84)

(D84)
At 0 ° C., a stirred solution of 1,4-dioxaspiro [4,5] decan-8-ol (D1, 8, 7 g, 55 mmol) in THF (110 ml) was added to sodium hydride (2.7 g of 60%, 66 mmol). The mixture was stirred at room temperature for 1 hour, then cooled to 0 ° C. and treated dropwise with carbon disulfide (7 ml, 110 mmol). The resulting mixture was stirred at room temperature for 3 hours, then cooled to 0 ° C., and iodomethane (4.12 ml, 66 mmol) was added dropwise. The resulting mixture was stirred for 1 hour at room temperature, then treated with aqueous NH ₄ Cl and extracted with Et ₂ O. The organic phase was separated and the aqueous layer was extracted twice with Et ₂ O. The combined organics were washed with a saturated NaCl solution containing a small amount of sodium hydrogen sulfide, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a yellow / orange oil (quantitative).
1H NMR (CDCl3, 400MHz): 1.62-1.72 (2H, m), 1.78-1.92 (2H, m), 1.95-2.06 (4H, m), 2.55 (3H, s), 3.92-4.02 (4H, m) , 5.64-5.74 (1H, m)

（Ｄ８５）
０℃にて、ジクロロメタン（５ｍｌ）、７０％ＨＦ−ピリジン（２ｍｌ）、Ｎ−ブロモスクシンイミド（１．８ｇ）およびピリジン（０．６ｍｌ）の混合物に、ジクロロメタン（５ｍｌ）中、Ｏ−１，４−ジオキサスピロ［４．５］デク−８−イルＳ−メチルジチオカーボネート（Ｄ８４、５００ｍｇ）の溶液を滴下した。０℃でさらに１時間後、この反応物を重炭酸ナトリウム水溶液およびｐＨ９の水酸化ナトリウムで洗浄した。 Description 85.8-[(trifluoromethyl) oxy] -1,4-dioxaspiro [4.5] decane (D85)

(D85)
At 0 ° C., a mixture of dichloromethane (5 ml), 70% HF-pyridine (2 ml), N-bromosuccinimide (1.8 g) and pyridine (0.6 ml) was added O-1,4 in dichloromethane (5 ml). -A solution of dioxaspiro [4.5] dec-8-yl S-methyldithiocarbonate (D84, 500 mg) was added dropwise. After an additional hour at 0 ° C., the reaction was washed with aqueous sodium bicarbonate and pH 9 sodium hydroxide.

  The exact same reaction was then performed replacing N-bromosuccinimide with 1,3-dibromo-5,5-dimethylhydantoin and the products of the two reactions were combined and chromatographed (20 g silica, 25% in hexanes). Of ethyl acetate) to give the title compound (400 mg).

（Ｄ８６）
氷浴温度にてアルゴン下、Ｎ−メチルピロリジノン（２０ｍｌ）中、１，４−ジオキサスピロ［４．５］デカン−８−オール（Ｄ１、４．０ｇ）、臭化シクロプロピルメチル（４．１ｇ）の攪拌溶液を水素化ナトリウム（６０％油分散物２．０ｇ）で少量ずつ処理した。この混合物を一晩室温まで温めた。この混合物を冷却し、メタノールで注意深く処理した後、水を加え、この混合物をヘキサンで抽出した。有機抽出液を水で洗浄した後、乾燥させ（Ｎａ_２ＳＯ_４）、溶媒を除去し、標題化合物を鉱油残渣が混入した油状物として得た（７．４９ｇ）。
¹HNMR δ(CDCl₃, 400 MHz): 0.18 (2H, m), 0.52 (2H, m), 0.85 (1H, m), 1.05 (1H, m), 1.55 (2H, m), 1.77-1.90 (4H, m), 3.25 (2H, m), 3.42 (1H, m), 3.95 (4H, m) Description 86.8-[(cyclopropylmethyl) oxy] -1,4-dioxaspiro [4.5] decane (D86)

(D86)
1,4-Dioxaspiro [4.5] decan-8-ol (D1, 4.0 g), cyclopropylmethyl bromide (4.1 g) in N-methylpyrrolidinone (20 ml) under argon at ice bath temperature Was stirred in portions with sodium hydride (2.0 g of a 60% oil dispersion). The mixture was warmed to room temperature overnight. After the mixture was cooled and carefully treated with methanol, water was added and the mixture was extracted with hexane. The organic extract was washed with water and then dried (Na ₂ SO ₄ ) and the solvent removed to give the title compound as an oil contaminated with mineral oil residue (7.49 g).
¹ HNMR δ (CDCl ₃ , 400 MHz): 0.18 (2H, m), 0.52 (2H, m), 0.85 (1H, m), 1.05 (1H, m), 1.55 (2H, m), 1.77-1.90 ( 4H, m), 3.25 (2H, m), 3.42 (1H, m), 3.95 (4H, m)

（Ｄ８７）
テトラヒドロフラン（１５ｍｌ）中、８−［（シクロプロピルメチル）オキシ］−１，４−ジオキサスピロ［４．５］デカン（Ｄ８６、７．４６ｇ）の溶液を５Ｍ ＨＣｌ（４０ｍｌ）で処理し、３時間攪拌した。得られた混合物をロータリーエバポレーターで部分的に濃縮し、水で希釈し、ジクロロメタンで抽出した（２回）。合わせた抽出液をブラインで洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、標題化合物を透明な油状物として得た（６．０９ｇ）。
¹H NMR δ(CDCl₃, 400 MHz): 0.22 (2H, m), 0.55 (2H, m), 0.88 (1H, m), 1.1 (1H, m)1.90-2.00 (2H, m), 2.05-2.13 (2H, m), 2.20-2.32 (2H, m), 2.53-2.65 (2H, m), 3.54 (2H, m), 3.74 (1H, m) Description 87.4-[(Cyclopropylmethyl) oxy] cyclohexanone (D87)

(D87)
A solution of 8-[(cyclopropylmethyl) oxy] -1,4-dioxaspiro [4.5] decane (D86, 7.46 g) in tetrahydrofuran (15 ml) was treated with 5M HCl (40 ml) and stirred for 3 hours. did. The resulting mixture was partially concentrated on a rotary evaporator, diluted with water and extracted with dichloromethane (twice). The combined extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a clear oil (6.09 g).
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.22 (2H, m), 0.55 (2H, m), 0.88 (1H, m), 1.1 (1H, m) 1.90-2.00 (2H, m), 2.05- 2.13 (2H, m), 2.20-2.32 (2H, m), 2.53-2.65 (2H, m), 3.54 (2H, m), 3.74 (1H, m)

（Ｄ８８）
アルゴン下、１，２−ジクロロエタン（２００ｍｌ）中、４−［（シクロプロピルメチル）オキシ］シクロヘキサノン（Ｄ８７、６．０９ｇ）の攪拌溶液を４−ピペリジニルカルバミン酸１，１−ジメチルエチル（７．２ｇ）、トリアセトキシ水素化ホウ素ナトリウム（９．８ｇ）で処理した後、得られた混合物を室温で３日間攪拌した。反応混合物をジクロロメタンで希釈した後、Ｎａ_２ＣＯ_３溶液（２回）、ブライン（２回）で洗浄し、その後、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残った黄色油状物を沸騰した６０〜８０石油エーテル（〜２００ｍｌ）に溶解し、室温で放置した。生じた結晶を濾別し、石油で洗浄し、乾燥させ、標題化合物のトランスおよびシス異性体混合物３．７１ｇを得た。この母液からさらなる生成物が得られた。Ｍ^＋＋Ｈ＝３５３ Description 88. (1- {4-[(Cyclopropylmethyl) oxy] cyclohexyl} -4-piperidinyl) carbamic acid cis / trans-1,1-dimethylethyl (D88)

(D88)
Under argon, a stirred solution of 4-[(cyclopropylmethyl) oxy] cyclohexanone (D87, 6.09 g) in 1,2-dichloroethane (200 ml) was added to 1,1-dimethylethyl 4-piperidinylcarbamate (7 0.2 g), sodium triacetoxyborohydride (9.8 g), and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with dichloromethane and then washed with Na ₂ CO ₃ solution (2 times), brine (2 times), then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The remaining yellow oil was dissolved in boiling 60-80 petroleum ether (-200 ml) and allowed to stand at room temperature. The resulting crystals were filtered off, washed with petroleum and dried to give 3.71 g of a trans and cis isomer mixture of the title compound. Additional product was obtained from this mother liquor. M ⁺ + H = 353

（Ｄ８９）
（１−｛４−［（シクロプロピルメチル）オキシ］シクロヘキシル｝−４−ピペリジニル）カルバミン酸シス／トランス−１，１−ジメチルエチル（Ｄ８８、３．７１ｇ）をメタノール（１５ｍｌ）に溶解し、塩化水素（２０ｍｌ）で飽和させたエタノール溶液で２時間処理した。溶媒を蒸発させ、標題化合物を白色固体として得た（３．２７ｇ）。Ｍ^＋＋Ｈ＝２５３ Description 89. Cis / trans-1- {4-[(cyclopropylmethyl) oxy] cyclohexyl} -4-piperidineamine dihydrochloride

(D89)
(1- {4-[(Cyclopropylmethyl) oxy] cyclohexyl} -4-piperidinyl) carbamic acid cis / trans-1,1-dimethylethyl (D88, 3.71 g) was dissolved in methanol (15 ml) and chlorinated. Treated with an ethanol solution saturated with hydrogen (20 ml) for 2 h. The solvent was evaporated to give the title compound as a white solid (3.27g). M ⁺ + H = 253

乾燥ジメチルホルムアミド（１０ｍｌ）中、シス／トランス−１−｛４−［（シクロプロピルメチル）オキシ］シクロヘキシル｝−４−ピペリジンアミン二塩酸塩（Ｄ８９、１．２０ｇ）、ジイソプロピルエチルアミン（３ｍｌ）および３−フルオロ−４−ニトロトルエン（１．１ｇ）の溶液をマイクロ波反応装置にて２００℃で２０分間加熱した。次に、この粗混合物を室温まで冷却し、ＳＣＸカートリッジに乗せた。このカートリッジをメタノール、次いで２Ｍメタノール性アンモニアで溶出した。メタノール性アンモニア画分を蒸発させて粗生成物を得、これをＢｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカカラムでのクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）により精製し、標題化合物のシスおよびトランス異性体を個別に得た。 Description 90.1- {trans-4-[(cyclopropylmethyl) oxy] cyclohexyl} -N- (5-methyl-2-nitrophenyl) -4-piperidineamine (D90a) and 1- {cis-4- [ (Cyclopropylmethyl) oxy] cyclohexyl} -N- (5-methyl-2-nitrophenyl) -4-piperidineamine (D90b)

Cis / trans-1- {4-[(cyclopropylmethyl) oxy] cyclohexyl} -4-piperidineamine dihydrochloride (D89, 1.20 g), diisopropylethylamine (3 ml) and 3 in dry dimethylformamide (10 ml) A solution of fluoro-4-nitrotoluene (1.1 g) was heated in a microwave reactor at 200 ° C. for 20 minutes. The crude mixture was then cooled to room temperature and loaded onto an SCX cartridge. The cartridge was eluted with methanol followed by 2M methanolic ammonia. Evaporation of the methanolic ammonia fraction gave a crude product that was purified by chromatography on a Biotage KP-NH ™ -silica column (ethyl acetate / n-hexane) to give the cis and trans isomers of the title compound. The body was obtained individually.

The fast eluting isomer (D90a; trans isomer) was obtained as an orange solid (0.616 g). MH ⁺ = 388
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.2 (2H, m), 0.55 (2H, m), 1.05 (1H, m), 1.4 (2H, m), 1.55-1.70 (obs, m), 1.97 (2H, m), 2.1 (2H, m), 2.45 (4H, m), 2.5 (2H, m), 2.9 (2H, m), 3.22 (2H, m), 3.52 (2H, m), 6.42 ( 1H, d), 6.62 (1H, s) 8.06 (1H, d), 8.2 (1H, d)

The slow eluting isomer (D90b; cis isomer) was obtained as a solid (0.417 g). MH ⁺ = 388
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.2 (2H, m), 0.5 (2H, m), 1.05 (1H, m), 1.3 (4H, m), 1.55-1.70 (obs, m), 1.9 (2H, m), 2.1 (4H, m), 2.35 (3H, m), 2.45 (2H, m), 3.2
(1H, m), 3.3 (2H, m), 3.56 (1H, m), 6.43 (1H, d), 6.61 (1H, s) 8.08 (1H, d), 8.2 (1H, d)

（Ｄ９１）
エタノール（３０ｍｌ）中、１−｛シス−−４−［（シクロプロピルメチル）オキシ］シクロヘキシル｝−Ｎ−（５−メチル−２−ニトロフェニル）−４−ピペリジンアミン（Ｄ９０ｂ、０．４１７ｇ）およびラネーニッケルの水性懸濁液（５０％懸濁液１ｍｌ）を、ヒドラジン水和物（１ｍｌ）の添加中、４０℃で攪拌した。この混合物を４０℃で３０分間攪拌し、冷却し、濾過した。濾液を蒸発させ、ジクロロメタンと共沸させ、標題化合物を白色固体として得た（３８０ｍｇ）。Ｍ^＋＋Ｈ＝３９４ Description 91. N ² - (1-{cis-4 - [(cyclopropylmethyl) oxy] cyclohexyl} -4-piperidinyl) -4-methyl-1,2-benzenediamine (D91)

(D91)
1- {cis-4--4-[(cyclopropylmethyl) oxy] cyclohexyl} -N- (5-methyl-2-nitrophenyl) -4-piperidinamine (D90b, 0.417 g) in ethanol (30 ml) and An aqueous suspension of Raney nickel (1 ml of 50% suspension) was stirred at 40 ° C. during the addition of hydrazine hydrate (1 ml). The mixture was stirred at 40 ° C. for 30 minutes, cooled and filtered. The filtrate was evaporated and azeotroped with dichloromethane to give the title compound as a white solid (380 mg). M ⁺ + H = 394

（Ｄ９２）
エタノール（３０ｍｌ）、メタノール（４０ｍｌ）およびラネーニッケルの水性懸濁液（５０％懸濁液１ｍｌ）中、１−｛トランス−４−［（シクロプロピルメチル）オキシ］シクロヘキシル｝−Ｎ−（５−メチル−２−ニトロフェニル）−４−ピペリジンアミン（Ｄ９０ａ、０．６１３ｇ）を、ヒドラジン水和物（１ｍｌ）の添加中、４０℃で攪拌した。この混合物を４０℃で３０分間攪拌し、冷却し、濾過した。濾液を蒸発させ、標題化合物を白色固体として得た（５７９ｍｇ）。Ｍ^＋＋Ｈ＝３９４ Description 92. N ² - (1-{trans-4 - [(cyclopropylmethyl) oxy] cyclohexyl} -4-piperidinyl) -4-methyl-1,2-benzenediamine (D92)

(D92)
1- {trans-4-[(cyclopropylmethyl) oxy] cyclohexyl} -N- (5-methyl) in an aqueous suspension of ethanol (30 ml), methanol (40 ml) and Raney nickel (1 ml of 50% suspension). -2-Nitrophenyl) -4-piperidinamine (D90a, 0.613 g) was stirred at 40 ° C. during the addition of hydrazine hydrate (1 ml). The mixture was stirred at 40 ° C. for 30 minutes, cooled and filtered. The filtrate was evaporated to give the title compound as a white solid (579 mg). M ⁺ + H = 394

（Ｄ９３）
室温にて、アセトニトリル（２０ｍｌ）中、トランスＮ−（４−ｔｅｒｔ−ブチルジメチルシリルオキシシクロヘキシル）フタルイミド（Ｄ４１、１．８ｇ、５ｍｍｏｌ）の溶液をトリエチルシラン（１．０ｍｌ、６ｍｍｏｌ）、三臭化ビスマス（２４０ｍｇ、０．５ｍｍｏｌ）およびシクロブタノン（０．４５ｍｌ、６ｍｍｏｌ）で順次処理した。さらに３０分後、この溶液を重炭酸ナトリウム水溶液／酢酸エチルで分液した。有機層を乾燥させ、蒸発させ、標題化合物をヘキサンから結晶化させた（８２０ｍｇ）。 Description 93. Trans N- (4-cyclobutyloxycyclohexyl) phthalimide (D93)

(D93)
At room temperature, a solution of trans N- (4-tert-butyldimethylsilyloxycyclohexyl) phthalimide (D41, 1.8 g, 5 mmol) in acetonitrile (20 ml) was triethylsilane (1.0 ml, 6 mmol), tribromide. Treated sequentially with bismuth (240 mg, 0.5 mmol) and cyclobutanone (0.45 ml, 6 mmol). After an additional 30 minutes, the solution was partitioned with aqueous sodium bicarbonate / ethyl acetate. The organic layer was dried and evaporated and the title compound was crystallized from hexane (820 mg).

（Ｄ９４）
トランスＮ−（４−シクロブチルオキシシクロヘキシル）フタルイミド（Ｄ９３、８２０ｍｇ、２．７ｍｍｏｌ）、ヒドラジン水和物（０．５ｍｌ、１０．０ｍｍｏｌ）およびエタノール（５ｍｌ）の混合物を８０℃で２時間加熱した後、冷却し、濾過した。濾液を蒸発させ、得られた残渣をジエチルエーテルに再溶解し、濾過し、再び蒸発させ、標題化合物を得た（１８０ｍｇ）。 Description 94. Trans 4-cyclobutyloxycyclohexylamine (D94)

(D94)
A mixture of trans N- (4-cyclobutyloxycyclohexyl) phthalimide (D93, 820 mg, 2.7 mmol), hydrazine hydrate (0.5 ml, 10.0 mmol) and ethanol (5 ml) was heated at 80 ° C. for 2 hours. Then it was cooled and filtered. The filtrate was evaporated and the resulting residue was redissolved in diethyl ether, filtered and evaporated again to give the title compound (180 mg).

（Ｄ９５）
トランス４−シクロブチルオキシシクロヘキシルアミン（Ｄ９４、１８０ｍｇ、１．１ｍｍｏｌ）、１−エチル−４−ピペリドンメチオジド（Ｄ４４、５４０ｍｇ、２．０ｍｍｏｌ）、炭酸カリウム（１５ｍｇ、０．１ｍｍｏｌ）、水（５ｍｌ）およびエタノール（１０ｍｌ）の混合物を８０℃で１時間加熱した後、冷却し、重炭酸ナトリウム水溶液／ジクロロメタンで分液し、クロマトグラフィー（２０ｇシリカ、０．２Ｍアンモニアを含有するジクロロメタン中０〜１０％メタノール）により精製し、標題化合物を得た（１５０ｍｇ）。 Description 95. Trans 1- [4- (cyclobutyloxy) -cyclohexyl] -4-piperidone (D95)

(D95)
Trans 4-cyclobutyloxycyclohexylamine (D94, 180 mg, 1.1 mmol), 1-ethyl-4-piperidone methiodide (D44, 540 mg, 2.0 mmol), potassium carbonate (15 mg, 0.1 mmol), water A mixture of (5 ml) and ethanol (10 ml) was heated at 80 ° C. for 1 hour, then cooled, partitioned with aqueous sodium bicarbonate / dichloromethane and chromatographed (20 g silica, 0 in dichloromethane containing 0.2 M ammonia. To 10% methanol) to give the title compound (150 mg).

（Ｄ９６）
トランス１−［４−（シクロブチルオキシ）−シクロヘキシル］−４−ピペリドン（Ｄ９５、１５０ｍｇ、０．６ｍｍｏｌ）、メタノール中２Ｍのアンモニア（１０ｍｌ、２０ｍｍｏｌ）および１０％パラジウム炭素ペースト（２０ｍｇ）の混合物を室温にて一晩５０ｐｓｉで水素化した後、濾過し、蒸発させ、標題化合物を得た（１３０ｍｇ）。 Description 96. Trans 1- [4- (Cyclobutyloxy) -cyclohexyl] -4-piperidinamine (D96)

(D96)
A mixture of trans 1- [4- (cyclobutyloxy) -cyclohexyl] -4-piperidone (D95, 150 mg, 0.6 mmol), 2M ammonia in methanol (10 ml, 20 mmol) and 10% palladium on carbon paste (20 mg). Hydrogenated at 50 psi overnight at room temperature, then filtered and evaporated to give the title compound (130 mg).

（Ｄ９７）
３−フルオロ−４−ニトロトルエン（８０ｍｇ）、ジメチルホルムアミド（２．５ｍｌ）、ジイソプロピルエチルアミン（０．１７ｍｌ）およびトランス１−［４−（シクロブチルオキシ）−シクロヘキシル］−４−ピペリジンアミン（Ｄ９６、１３０ｍｇ、０．５ｍｍｏｌ）の混合物を８０℃で一晩加熱した。冷却反応物を酢酸エチルで希釈し、水で３回洗浄した後、乾燥させ、蒸発させ、クロマトグラフィーに付し（５ｇシリカ、０．２Ｍアンモニアを含有するジクロロメタン中０〜５％メタノール）、標題化合物を得た（６０ｍｇ）。 Description 97. Trans N- (5-methyl-2-nitrophenyl) -1- (4-cyclobutyloxycyclohexyl) -4-piperidinamine (D97)

(D97)
3-Fluoro-4-nitrotoluene (80 mg), dimethylformamide (2.5 ml), diisopropylethylamine (0.17 ml) and trans 1- [4- (cyclobutyloxy) -cyclohexyl] -4-piperidineamine (D96, 130 mg) , 0.5 mmol) was heated at 80 ° C. overnight. The cooled reaction was diluted with ethyl acetate and washed three times with water, then dried, evaporated and chromatographed (5 g silica, 0-5% methanol in dichloromethane containing 0.2 M ammonia). Compound was obtained (60 mg).

（Ｄ９８）
５０℃にて、エタノール（５ｍｌ）中、トランスＮ−（５−メチル−２−ニトロフェニル）−１−（４−ｃｙｃＩＩブチルオキシシクロヘキシル）−４−ピペリジンアミン（Ｄ９７、６０ｍｇ、０．１６ｍｍｏｌ）の攪拌懸濁液をラネーニッケル（１０％水性懸濁液１．０ｍｌ）で処理した後、ヒドラジン水和物（０．０８ｍｌ）を滴下した。この混合物を同じ温度で１時間加熱した後、Ｋｉｅｓｅｌｇｕｈｒで濾過し、濾液を蒸発させ、トルエン、次いでジエチルエーテルから再蒸発させ、標題化合物を得た（５０ｍｇ）。 Description 98. Trans 5-methyl-N- [1- (4-cyclobutyloxycyclohexyl) -4-piperidinyl] -1,2-benzenediamine (D98)

(D98)
Of trans N- (5-methyl-2-nitrophenyl) -1- (4-cycII butyloxycyclohexyl) -4-piperidinamine (D97, 60 mg, 0.16 mmol) in ethanol (5 ml) at 50 ° C. The stirred suspension was treated with Raney nickel (1.0 ml of 10% aqueous suspension), and hydrazine hydrate (0.08 ml) was added dropwise. The mixture was heated at the same temperature for 1 hour then filtered through Kieselguhr and the filtrate was evaporated and re-evaporated from toluene then diethyl ether to give the title compound (50 mg).

（Ｄ９９） 室温にて、ジメチルホルムアミド（２０ｍｌ）中、４−ブロモ−２−フルオロ−１−ニトロベンゼン（３００ｍｇ、１．３６ｍｍｏｌ）および１−［トランス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ４９、４２２ｍｇ、１．３６ｍｍｏｌ）の混合物をジイソプロピルエチルアミン（０．８ｍｌ，３当量）で処理した後、アルゴン下、９０℃で５時間加熱した。この混合物を水および飽和ＮａＨＣＯ_３溶液で洗浄した後、ジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残渣をＳＣＸカートリッジに乗せ、まずジクロロメタン、次いで２Ｍ ＮＨ_３／ＭｅＯＨで溶出して生成物を取り出し、これを真空濃縮し、標題化合物を得た（６１０ｍｇ、９９％）。ＭＨ＋＝４４１、４４２
¹H NMR δ(CDCl₃, 400MHz): 0.91 (3H, t), 1.18-1.40 (4H, m), 1.51-1.72 (4H, mと仮定), 1.85-1.97 (2H, m), 2.02-2.18 (4H, m), 2.29-2.39 (1H, m), 2.39-2.50 (2H, m), 2.84-2.94 (2H, m), 3.10-3.20 (1H, m), 3.40 (2H, t), 3.41-3.55 (1H, m), 6.73 (1H, dd), 7.00 (1H, d), 8.03 (1H, d), 8.13 (1H, d) Description 99. N- (5-bromo-2-nitrophenyl) -1- [trans-4- (propyloxy) cyclohexyl] -4-piperidineamine (D99)

(D99) 4-Bromo-2-fluoro-1-nitrobenzene (300 mg, 1.36 mmol) and 1- [trans-4- (propyloxy) cyclohexyl] -4-piperidine in dimethylformamide (20 ml) at room temperature. A mixture of amine dihydrochloride (D49, 422 mg, 1.36 mmol) was treated with diisopropylethylamine (0.8 ml, 3 eq) and then heated at 90 ° C. under argon for 5 hours. The mixture was washed with water and saturated NaHCO ₃ solution and then extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was loaded onto an SCX cartridge, eluting with dichloromethane and then 2M NH ₃ / MeOH to remove the product, which was concentrated in vacuo to give the title compound (610 mg, 99%). MH + = 441, 442
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.91 (3H, t), 1.18-1.40 (4H, m), 1.51-1.72 (assuming 4H, m), 1.85-1.97 (2H, m), 2.02-2.18 (4H, m), 2.29-2.39 (1H, m), 2.39-2.50 (2H, m), 2.84-2.94 (2H, m), 3.10-3.20 (1H, m), 3.40 (2H, t), 3.41 -3.55 (1H, m), 6.73 (1H, dd), 7.00 (1H, d), 8.03 (1H, d), 8.13 (1H, d)

（Ｄ１００）
室温にてアルゴン下、エタノール（１００ｍｌ）中、Ｎ−（５−ブロモ−２−ニトロフェニル）−１−［トランス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ９９、６２０ｍｇ、１．４１ｍｍｏｌ）の攪拌溶液をラネーニッケル（８０ｍｇ）で処理し、ヒドラジン水和物（１．１ｍｌ、３５．２５ｍｍｏｌ）を滴下し、３時間維持した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過し、濾液を真空濃縮し、標題化合物を褐色油状物として得た（５７４ｍｇ、９９％）。ＭＨ＋＝４１１、４１２
¹H NMR δ(CDCl₃, 400MHz): 0.90 (3H, t), 1.20-1.40 (4H, m), 1.40-1.65 (4H, m), 1.85-1.98 (2H, m), 2.01-2.15 (4H, m), 2.26-2.40 (3H, m), 2.85-2.95 (2H, m), 3.05-3.45 (5H, m), 3.40 (2H, t), 6.57 (1H, m), 6.69-6.76 (2H, m) Wherein 100.4- Bromo ^-N 2 - {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D100)

(D100)
N- (5-Bromo-2-nitrophenyl) -1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinamine (D99, 620 mg, 1. A stirred solution of 41 mmol) was treated with Raney nickel (80 mg) and hydrazine hydrate (1.1 ml, 35.25 mmol) was added dropwise and maintained for 3 hours. The mixture was filtered through Kieselguhr and the filtrate was concentrated in vacuo to give the title compound as a brown oil (574 mg, 99%). MH + = 411, 412
¹ H NMR δ (CDCl ₃ , 400MHz): 0.90 (3H, t), 1.20-1.40 (4H, m), 1.40-1.65 (4H, m), 1.85-1.98 (2H, m), 2.01-2.15 (4H , m), 2.26-2.40 (3H, m), 2.85-2.95 (2H, m), 3.05-3.45 (5H, m), 3.40 (2H, t), 6.57 (1H, m), 6.69-6.76 (2H , m)

（Ｄ１０１）
室温にてアルゴン下、トルエン（１０ｍｌ）中、Ｎ−（５−ブロモ−２−ニトロフェニル）−１−［トランス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ９９、３４０ｍｇ、０．７７ｍｍｏｌ）およびトリブチルビニルスズ（０．２８ｍｌ、０．８９ｍｍｏｌ）の溶液をトリフェニルホスフィン（５１ｍｇ、０．１９ｍｍｏｌ）およびビス（ジベンジリデン）アセトン）パラジウム（０）（６８ｍｇ、０．１２ｍｍｏｌ）で処理し、１２０℃で一晩加熱した。この混合物を冷却した後、Ｋｉｅｓｅｌｇｕｈｒで濾過し、真空濃縮した。残渣をジクロロメタンに溶解し、１０％水酸化アンモニウム水溶液で洗浄した後、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残渣をジクロロメタンに溶解し、ＳＣＸカートリッジを通して溶出させた後、２Ｍ ＮＨ_３／ＭｅＯＨでの溶出により回収し、濃縮した。残渣を、５〜３０％溶媒を用い、２５＋Ｍ Ｂｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカカラムでのクロマトグラフィーに付し、標題化合物を黄色固体として得た（２４０ｍｇ、８０％）。ＭＨ＋＝３８８
¹H NMR δ(CDCl₃, 400MHz): 0.91 (3H, t), 1.20-1.38 (4H, m), 1.52-1.72 (4H, mと仮定), 1.88-1.97 (2H, m), 2.03-2.16 (4H, m), 2.29-2.39 (1H, m), 2.39-2.50 (2H, m), 2.82-2.92 (2H, m), 3.10-3.21 (1H, m), 3.39 (2H, t), 3.52-3.63 (1H, t), 5.46 (1H, d), 5.87 (1H, d), 6.66 (1H, dd), 6.71-6.76 (2H, m), 8.15 (1H, d), 8.22 (1H, d) Description 101. N- (5-ethenyl-2-nitrophenyl) -1- [trans-4- (propyloxy) cyclohexyl] -4-piperidineamine (D101)

(D101)
N- (5-Bromo-2-nitrophenyl) -1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinamine (D99, 340 mg, 0. 0) in toluene (10 ml) under argon at room temperature. 77 mmol) and tributylvinyltin (0.28 ml, 0.89 mmol) were treated with triphenylphosphine (51 mg, 0.19 mmol) and bis (dibenzylidene) acetone) palladium (0) (68 mg, 0.12 mmol). , Heated at 120 ° C. overnight. After cooling the mixture, it was filtered through Kieselguhr and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with 10% aqueous ammonium hydroxide, then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dissolved in dichloromethane and eluted through an SCX cartridge, then collected by elution with 2M NH ₃ / MeOH and concentrated. The residue was chromatographed on a 25 + M Biotage KP-NH ™ -silica column with 5-30% solvent to give the title compound as a yellow solid (240 mg, 80%). MH + = 388
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.91 (3H, t), 1.20-1.38 (4H, m), 1.52-1.72 (assuming 4H, m), 1.88-1.97 (2H, m), 2.03-2.16 (4H, m), 2.29-2.39 (1H, m), 2.39-2.50 (2H, m), 2.82-2.92 (2H, m), 3.10-3.21 (1H, m), 3.39 (2H, t), 3.52 -3.63 (1H, t), 5.46 (1H, d), 5.87 (1H, d), 6.66 (1H, dd), 6.71-6.76 (2H, m), 8.15 (1H, d), 8.22 (1H, d )

（Ｄ１０２）
室温にてアルゴン下で１０分間、メタノール（２５ｍｌ）中、Ｎ−（５−エテニル−２−ニトロフェニル）−１−［トランス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ１０１、２４０ｍｇ、０．６１ｍｍｏｌ）およびギ酸アンモニウム（３８２．７ｍｇ、６．１ｍｍｏｌ）の混合物を攪拌した後、１０％Ｐｄ／Ｃ（１３６ｍｇ、０．２当量）で処理し、３０分間攪拌した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過し、濃縮して溶媒を除去した。残渣をジクロロメタンに溶解し、２Ｍ ＮａＯＨ溶液で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、標題化合物を紫色の粘稠な油状物として得た（１８０ｍｇ、８２％）。ＭＨ＋＝３６０
¹H NMR δ(CDCl₃, 400MHz): 0.91 (3H, t), 1.16-1.38 (7H, m), 1.42-1.62 (4H, m), 1.88-1.97 (2H, m), 2.01-2.12 (4H, m), 2.25-2.42 (3H, m), 2.53 (2H, q), 2.84-2.94 (2H, m), 2.95-3.40 (5H, m), 3.40 (2H, t), 6.47-6.61 (2H, m), 6.65 (1H, d) Wherein 102.4- ethyl ^-N 2 - {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D102)

(D102)
N- (5-ethenyl-2-nitrophenyl) -1- [trans-4- (propyloxy) cyclohexyl] -4-piperidineamine (D101, 240 mg) in methanol (25 ml) under argon at room temperature for 10 minutes , 0.61 mmol) and ammonium formate (382.7 mg, 6.1 mmol) were stirred and then treated with 10% Pd / C (136 mg, 0.2 eq) and stirred for 30 minutes. The mixture was filtered through Kieselguhr and concentrated to remove the solvent. The residue was dissolved in dichloromethane, washed with 2M NaOH solution, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a purple viscous oil (180 mg, 82%). MH + = 360
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.91 (3H, t), 1.16-1.38 (7H, m), 1.42-1.62 (4H, m), 1.88-1.97 (2H, m), 2.01-2.12 (4H , m), 2.25-2.42 (3H, m), 2.53 (2H, q), 2.84-2.94 (2H, m), 2.95-3.40 (5H, m), 3.40 (2H, t), 6.47-6.61 (2H , m), 6.65 (1H, d)

（Ｄ１０３）
ジメチルホルムアミド（１０ｍｌ）中、４−シクロプロピル−２−フルオロ−１−ニトロベンゼン（１００ｍｇ、０．５５ｍｍｏｌ）および１−［トランス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ４９、１７０ｍｇ、１当量）の混合物をジイソプロピルエチルアミン（０．２８ｍｌ）で処理した後、アルゴン下、８０℃で一晩加熱および攪拌した。この溶液を水で洗浄した後、ジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残渣をジクロロメタンに溶解し、ＳＣＸカートリッジを通し、まずジクロロメタン、次いで２Ｍ ＮＨ_３／ＭｅＯＨで溶出した。このメタノール溶液を真空濃縮して暗橙色固体を得（１４０ｍｇ）、これを５〜３０％ＥｔＯＡｃ／ヘキサンで溶出する４０＋Ｍ Ｂｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカカラムでのクロマトグラフィーにより精製し、標題化合物を橙色固体として得た（１１０ｍｇ、５０％）。ＭＨ＋＝４０２
¹H NMR δ(CDCl₃, 400MHz): 0.76-0.82 (2H, m), 0.90 (3H, t), 1.03-1.11 (2H, m), 1.19-1.40 (4H, mと仮定), 1.52-1.72 (4H, mと仮定), 1.82-1.98 (3H, mと仮定), 2.02-2.15 (4H, m), 2.18-2.39 (1H, m), 2.40-2.50 (2H, m), 2.80-2.92 (2H, m), 3.10-3.20 (1H, m), 3.40 (2H, t), 3.50-3.60 (1H, m), 6.19 (1H, dd), 6.55 (1H, d), 8.05 (1H, d), 8.21 (1H, d) Description 103. N- (5-cyclopropyl-2-nitrophenyl) -1- [trans-4- (propyloxy) cyclohexyl] -4-piperidineamine (D103)

(D103)
4-Cyclopropyl-2-fluoro-1-nitrobenzene (100 mg, 0.55 mmol) and 1- [trans-4- (propyloxy) cyclohexyl] -4-piperidineamine dihydrochloride (D49) in dimethylformamide (10 ml) , 170 mg, 1 eq) was treated with diisopropylethylamine (0.28 ml) and then heated and stirred at 80 ° C. under argon overnight. The solution was washed with water and extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dissolved in dichloromethane and passed through a SCX cartridge, eluting first with dichloromethane and then with 2M NH ₃ / MeOH. The methanol solution was concentrated in vacuo to give a dark orange solid (140 mg) which was purified by chromatography on a 40 + M Biotage KP-NH ™ -silica column eluting with 5-30% EtOAc / hexanes to give the title compound Was obtained as an orange solid (110 mg, 50%). MH + = 402
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.76-0.82 (2H, m), 0.90 (3H, t), 1.03-1.11 (2H, m), 1.19-1.40 (assuming 4H, m), 1.52-1.72 (Assuming 4H, m), 1.82-1.98 (assuming 3H, m), 2.02-2.15 (4H, m), 2.18-2.39 (1H, m), 2.40-2.50 (2H, m), 2.80-2.92 ( 2H, m), 3.10-3.20 (1H, m), 3.40 (2H, t), 3.50-3.60 (1H, m), 6.19 (1H, dd), 6.55 (1H, d), 8.05 (1H, d) , 8.21 (1H, d)

（Ｄ１０４）
室温にてアルゴン下、エタノール（２０ｍｌ）中、Ｎ−（５−シクロプロピル−２−ニトロフェニル）−１−［トランス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ１０３、１１０ｍｇ、０．２７ｍｍｏｌの攪拌溶液をラネーニッケル（３０ｍｇ）で処理し、ヒドラジン水和物（０．２ｍｌ、６．７５ｍｍｏｌ）を滴下し、２時間維持した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過し、濾液を真空濃縮し、標題化合物を緑色／黄色油状物として得た（７０ｍｇ、７０％）。ＭＨ＋＝３７２ Wherein 104.4- cyclopropyl ^-N 2 - {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D104)

(D104)
N- (5-cyclopropyl-2-nitrophenyl) -1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinamine (D103, 110 mg, 0 in ethanol (20 ml) at room temperature under argon. .27 mmol of the stirred solution was treated with Raney nickel (30 mg), hydrazine hydrate (0.2 ml, 6.75 mmol) was added dropwise and maintained for 2 hours, the mixture was filtered through Kieselguhr, the filtrate was concentrated in vacuo, The title compound was obtained as a green / yellow oil (70 mg, 70%) MH + = 372.

（Ｄ１０５）
室温にてアルゴン下、ジメチルホルムアミド（３ｍｌ）中、１−［シス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジンアミン（Ｄ６２、１４０ｍｇ、０．５８ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（０．１２４ｍｌ、０．７０ｍｍｏｌ）および３−フルオロ−４−ニトロトルエン（１２４ｍｇ、０．８０ｍｍｏｌ）で処理し、８０℃で１８時間加熱した。この混合物を真空濃縮し、残渣を１０％Ｎａ_２ＣＯ_３溶液で処理し、ジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、残渣を０〜１０％メタノール／ジクロロメタンで溶出するｏｎシリカゲル（１０ｇ）でのクロマトグラフィーに付し、標題化合物を黄色油状物として得た（１７０ｍｇ、７８％）。ＭＨ^＋３７６
¹H NMR δ(CDCl₃, 400 MHz): 0.85 (3H, s), 1.05-1.20 (2H, m), 1.21 (3H, t), 1.60-1.72 (6H, m), 1.90-2.00 (2H, m), 2.00-2.10 (2H, m), 2.28-2.40 (2H, m), 2.33 (3H, s), 2.80-2.90 (2H, m), 3.22-3.32 (1H, m), 3.47-3.57 (3H, t + m), 6.41 (1H, dd), 6.62 (1H, s), 8.06 (1H, d), 8.19 (1H, d) Description 105.1- [cis-4- (ethyloxy) -1-methylcyclohexyl] -N- (5-methyl-2-nitrophenyl) -4-piperidinamine (D105)

(D105)
A stirred solution of 1- [cis-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidineamine (D62, 140 mg, 0.58 mmol) in dimethylformamide (3 ml) at room temperature under argon was diluted with diisopropylethylamine (D62, 140 mg, 0.58 mmol). 0.124 ml, 0.70 mmol) and 3-fluoro-4-nitrotoluene (124 mg, 0.80 mmol) and heated at 80 ° C. for 18 hours. The mixture was concentrated in vacuo and the residue was treated with 10% Na ₂ CO ₃ solution and extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ), concentrated in vacuo and the residue was chromatographed on silica gel (10 g) eluting with 0-10% methanol / dichloromethane to give the title compound as a yellow oil. (170 mg, 78%). MH ⁺ 376
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.85 (3H, s), 1.05-1.20 (2H, m), 1.21 (3H, t), 1.60-1.72 (6H, m), 1.90-2.00 (2H, m), 2.00-2.10 (2H, m), 2.28-2.40 (2H, m), 2.33 (3H, s), 2.80-2.90 (2H, m), 3.22-3.32 (1H, m), 3.47-3.57 ( 3H, t + m), 6.41 (1H, dd), 6.62 (1H, s), 8.06 (1H, d), 8.19 (1H, d)

（Ｄ１０６）
室温にてアルゴン下、エタノール（１２ｍｌ）中、１−［シス−４−（エチルオキシ）−１−メチルシクロヘキシル］−Ｎ−（５−メチル−２−ニトロフェニル）−４−ピペリジンアミン（Ｄ１０５、１７０ｍｇ、０．４５ｍｍｏｌ）の攪拌溶液をラネーニッケル（〜２０ｍｇ）、次いでヒドラジン水和物（０．１５ｍｌ、４．８ｍｍｏｌ）で処理し、２時間維持した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過して触媒を除去し、濾液を真空濃縮し、標題化合物を淡灰色の油状物として得た（１５０ｍｇ、収率９６％）。ＭＨ^＋３４６
¹H NMR δ(CDCl₃, 400MHz): 0.85 (3H, s), 1.05-1.15 (2H, m), 1.20 (3H, t), 1.40-1.52 (2H, m), 1.60-1.75 (4H, m), 1.90-2.00 (2H, m), 2.00-2.10 (2H, m), 2.18-2.30 (2H, m), 2.25 (3H, s), 2.85-2.92 (2H, m), 3.00-3.35 (5H, m), 3.50 (2H, q), 6.44-6.50 (2H, m), 6.62 (1H, d) Description 106. N ² - {1- [cis-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -4-methyl-1,2-benzenediamine (D106)

(D106)
1- [cis-4- (Ethyloxy) -1-methylcyclohexyl] -N- (5-methyl-2-nitrophenyl) -4-piperidinamine (D105, 170 mg) in ethanol (12 ml) under argon at room temperature. , 0.45 mmol) was treated with Raney nickel (˜20 mg) followed by hydrazine hydrate (0.15 ml, 4.8 mmol) and maintained for 2 hours. The mixture was filtered through Kieselguhr to remove the catalyst and the filtrate was concentrated in vacuo to give the title compound as a light gray oil (150 mg, 96% yield). MH ⁺ 346
¹ H NMR δ (CDCl ₃ , 400MHz): 0.85 (3H, s), 1.05-1.15 (2H, m), 1.20 (3H, t), 1.40-1.52 (2H, m), 1.60-1.75 (4H, m ), 1.90-2.00 (2H, m), 2.00-2.10 (2H, m), 2.18-2.30 (2H, m), 2.25 (3H, s), 2.85-2.92 (2H, m), 3.00-3.35 (5H , m), 3.50 (2H, q), 6.44-6.50 (2H, m), 6.62 (1H, d)

（Ｄ１０７）
室温にてアルゴン下、ジメチルホルムアミド（５ｍｌ）中、１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジンアミン（Ｄ５８遊離塩基、２００ｍｇ、０．８３ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（０．２８ｍｌ、１．６ｍｍｏｌ）および３−フルオロ−４−ニトロトルエン（１７０ｍｇ、１．１ｍｍｏｌ）で処理し、８０℃で１８時間加熱した。この混合物を真空濃縮し、残渣を１０％Ｎａ_２ＣＯ_３溶液で処理し、ジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、残渣を０〜１０％メタノール／ジクロロメタンで溶出するシリカゲル（１０ｇ）でのクロマトグラフィーに付し、標題化合物を黄色油状物として得た（１８０ｍｇ、５８％）。ＭＨ^＋３７６
¹H NMR δ(CDCl₃, 400 MHz): 0.93 (3H, s), 1.20 (3H, t), 1.40-1.70 (8H, m), 1.80-1.90 (2H, m), 2.02-2.12 (2H, m), 2.28-2.38 (2H, m), 2.33 (3H, s), 2.90-2,98 (2H, m), 3.34-3.42 (1H, m), 3.45-3.58 (3H, q + m), 6.42 (1H, dd), 6.62 (1H, s), 8.05 (1H, d), 8.17 (1H, d) Description 107.1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -N- (5-methyl-2-nitrophenyl) -4-piperidinamine (D107)

(D107)
A stirred solution of 1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinamine (D58 free base, 200 mg, 0.83 mmol) in dimethylformamide (5 ml) under argon at room temperature. Treated with ethylamine (0.28 ml, 1.6 mmol) and 3-fluoro-4-nitrotoluene (170 mg, 1.1 mmol) and heated at 80 ° C. for 18 hours. The mixture was concentrated in vacuo and the residue was treated with 10% Na ₂ CO ₃ solution and extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ), concentrated in vacuo, and the residue was chromatographed on silica gel (10 g) eluting with 0-10% methanol / dichloromethane to give the title compound as a yellow oil ( 180 mg, 58%). MH ⁺ 376
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.93 (3H, s), 1.20 (3H, t), 1.40-1.70 (8H, m), 1.80-1.90 (2H, m), 2.02-2.12 (2H, m), 2.28-2.38 (2H, m), 2.33 (3H, s), 2.90-2,98 (2H, m), 3.34-3.42 (1H, m), 3.45-3.58 (3H, q + m), 6.42 (1H, dd), 6.62 (1H, s), 8.05 (1H, d), 8.17 (1H, d)

（Ｄ１０８）
室温にてアルゴン下、エタノール（１２ｍｌ）中、１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−Ｎ−（５−メチル−２−ニトロフェニル）−４−ピペリジンアミン（Ｄ１０７、１８０ｍｇ、０．４８ｍｍｏｌ）の攪拌溶液をラネーニッケル（〜２０ｍｇ）、次いでヒドラジン水和物（０．１５ｍｌ、４．８ｍｍｏｌ）で処理し、２時間維持した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過して触媒を除去し、濾液を真空濃縮し、標題化合物を極めて薄い黄色油状物として得た（１６０ｍｇ、収率９７％）。ＭＨ^＋３４６
¹H NMR δ(CDCl₃, 400MHz): 0.92 (3H, s), 1.20 (3H, t), 1.38-1.57 (6H, m), 1.62-1.72 (2H, m), 1.80-1.90 (2H, m), 2.07 (2H, br d), 2.22-2.32 (2H, m), 2.24 (3H, s), 2.96 (2H, br d), 3.00-3.30 (4H, m), 3.33-3.38 (1H, m), 3.48 (2H, q), 6.42-6.50 (2H, m), 6.62 (1H, d) Description 108. N ² - {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -4-methyl-1,2-benzenediamine (D108)

(D108)
1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -N- (5-methyl-2-nitrophenyl) -4-piperidinamine (D107, 180 mg) in ethanol (12 ml) under argon at room temperature. , 0.48 mmol) was treated with Raney nickel (˜20 mg) followed by hydrazine hydrate (0.15 ml, 4.8 mmol) and maintained for 2 hours. The mixture was filtered through Kieselguhr to remove the catalyst and the filtrate was concentrated in vacuo to give the title compound as a very pale yellow oil (160 mg, 97% yield). MH ⁺ 346
¹ H NMR δ (CDCl ₃ , 400MHz): 0.92 (3H, s), 1.20 (3H, t), 1.38-1.57 (6H, m), 1.62-1.72 (2H, m), 1.80-1.90 (2H, m ), 2.07 (2H, br d), 2.22-2.32 (2H, m), 2.24 (3H, s), 2.96 (2H, br d), 3.00-3.30 (4H, m), 3.33-3.38 (1H, m ), 3.48 (2H, q), 6.42-6.50 (2H, m), 6.62 (1H, d)

（Ｄ１０９）
三口フラスコにディーン・スタークトラップとアルゴン接続冷却器を取り付けた。このフラスコに４−ピペリジニルカルバミン酸１，１−ジメチルエチル（１．１当量、７ｍｍｏｌ、１．４ｇ）、４−（プロピルオキシ）シクロヘキサノン（Ｄ１９、１当量、６．４ｍｍｏｌ、１ｇ）、１，２，３−トリアゾール（１．２当量、７．７ｍｍｏｌ、０．５３ｇ）および５０ｍｌの乾燥トルエンを入れた。この混合物をアルゴン下、１３０℃で６時間還流させた後、室温まで冷却し、臭化メチルマグネシウム溶液（Ｅｔ_２Ｏ中３Ｍ）（４当量、２５．６ｍｍｏｌ、８．５ｍｌ）を、２５℃を超えないように２０分かけて加えた。固体の沈殿が見られ、５０ｍｌ過剰のテトラヒドロフランを加え、氷浴で温度を厳密に１０℃に維持した。この混合物を室温で一晩攪拌した。次に、この混合物を０℃まで冷却し、飽和塩化アンモニウム水溶液でゆっくりクエンチした。その後、この混合物を室温にし、ＥｔＯＡｃで希釈し、２層に分けた。水相をＥｔＯＡｃで抽出し（２回）、有機液を合わせ、硫酸ナトリウムで乾燥させ、濾過し、溶媒を蒸発させて粗生成物を得、これを次にシリカゲルクロマトグラフィー（ＭｅＯＨ−ＮＨ_３−ＤＣＭ）により精製し、標題化合物を黄色油状物として得た（０．６６ｇ、３０％）。Ｍ^＋＋Ｈ＝３５５ Description 109. {1- [1-Methyl-4- (propyloxy) cyclohexyl] -4-piperidinyl} carbamic acid cis / trans 1,1-dimethylethyl (D109)

(D109)
A three-necked flask was equipped with a Dean-Stark trap and an argon connected condenser. To this flask was added 1,1-dimethylethyl 4-piperidinylcarbamate (1.1 eq, 7 mmol, 1.4 g), 4- (propyloxy) cyclohexanone (D19, 1 eq, 6.4 mmol, 1 g), 1 , 2,3-triazole (1.2 eq, 7.7 mmol, 0.53 g) and 50 ml of dry toluene. The mixture was refluxed at 130 ° C. under argon for 6 hours, then cooled to room temperature and methylmagnesium bromide solution (3M in Et ₂ O) (4 eq, 25.6 mmol, 8.5 ml) was added at 25 ° C. It was added over 20 minutes so as not to exceed. A solid precipitate was seen, 50 ml excess of tetrahydrofuran was added and the temperature was kept strictly 10 ° C. in an ice bath. The mixture was stirred at room temperature overnight. The mixture was then cooled to 0 ° C. and slowly quenched with saturated aqueous ammonium chloride. The mixture was then brought to room temperature, diluted with EtOAc and separated into two layers. The aqueous phase was extracted with EtOAc (twice), the organics were combined, dried over sodium sulfate, filtered and the solvent was evaporated to give the crude product, which was then chromatographed on silica gel (MeOH—NH ₃ − DCM) gave the title compound as a yellow oil (0.66 g, 30%). M ⁺ + H = 355

（Ｄ１１０）
｛１−［１−メチル−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジニル｝カルバミン酸シス／トランス１，１−ジメチルエチル（Ｄ１０９、０．６６ｇ、１．８ｍｍｏｌ）をＥｔ_２Ｏ（１０ｍｌ）に溶解し、室温でＨＣｌ（１，４−ジオキサン中４Ｍ溶液５ｍｌ）を加えた。この混合物を室温で６時間攪拌した。次に、溶媒を蒸発させて粗生成物（４４０ｍｇ）を得、これをそのまま次の工程に用いた。Ｍ^＋＋Ｈ＝２５５ Description 110. Cis / trans 1- [1-methyl-4- (propyloxy) cyclohexyl] -4-piperidineamine dihydrochloride (D110)

(D110)
{1- [1-Methyl-4- (propyloxy) cyclohexyl] -4-piperidinyl} carbamic acid cis / trans 1,1-dimethylethyl (D109, 0.66 g, 1.8 mmol) was added to Et ₂ O (10 ml). And HCl (5 ml of a 4M solution in 1,4-dioxane) was added at room temperature. The mixture was stirred at room temperature for 6 hours. The solvent was then evaporated to give the crude product (440 mg) which was used as such for the next step. M ⁺ + H = 255

シス／トランス１−［１−メチル−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ１１０、１当量、４４０ｍｇ、１．３ｍｍｏｌ）をジメチルホルムアミド（４ｍｌ）に溶解し、室温にて、Ｈｕｎｉｇｈ塩基（３当量、０．６８ｍｌ）、次いで２−フルオロ−４−メチル−１−ニトロベンゼン（１当量、２００ｍｇ）を加え、この混合物を１００℃で一晩攪拌した。次に、この粗混合物を室温まで冷却し、水／ブラインに注いだ。この水溶液をＥｔＯＡで抽出し（３回）、有機液を水（１回）およびブライン（１回）で交互に洗浄した。有機液を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させて粗生成物を得、これをクロマトグラフィーおよびＳＣＸカートリッジにより精製し、２つの分離した標題化合物異性体を得た（シス５７ｍｇ、およびトランス４９ｍｇ）。Ｍ^＋＋Ｈ＝３９０
シス異性体（Ｄ１１１ａ）：¹HNMR δ(DMSO, 500 MHz): 0.868 (6H, m), 1.392 (2H, m ブロード), 1.478 (8H, m), 1.739 (2H, m), 1.992 (2H, d), 2.294 (5H, m), 2.821 (2H, d), 3.300 (ウォーターピーク下2H), 3.359 (1H, s ブロード), 3.646 (1H, s ブロード), 6.504 (1H, d), 6.932 (1H, s), 7.954 (1H, d), 8.023 (1H, d)
トランス異性体（Ｄ１１１ｂ）：¹HNMR δ(DMSO, 500 MHz): 0.849 (6H, m), 1.107 (2H, t), 1.499 (8H, m), 1.869 (2H, d), 1.993 (2H, d), 2.886 (5H, m), 2.790 (2H, d), 3.197 (1H, m), 3.315 (ウォーターピーク下2H), 3.652 (1H, m ブロード), 6.505 (1H, d), 6.936 (1H, s), 7.957 (1H, d), 8.040 (1H, d) Description 111. Cis and trans N- (5-methyl-2-nitrophenyl) -1- [1-methyl-4- (propyloxy) cyclohexyl] -4-piperidineamine (cis = D111a; trans = D111b)

Cis / trans 1- [1-methyl-4- (propyloxy) cyclohexyl] -4-piperidineamine dihydrochloride (D110, 1 eq, 440 mg, 1.3 mmol) was dissolved in dimethylformamide (4 ml) at room temperature. Hunigh base (3 eq, 0.68 ml) was added followed by 2-fluoro-4-methyl-1-nitrobenzene (1 eq, 200 mg) and the mixture was stirred at 100 ° C. overnight. The crude mixture was then cooled to room temperature and poured into water / brine. The aqueous solution was extracted with EtOA (3 times) and the organics were washed alternately with water (1 time) and brine (1 time). The organics were combined, dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated to give the crude product, which was purified by chromatography and SCX cartridge to give two separate title compound isomers ( Cis 57 mg, and trans 49 mg). M ⁺ + H = 390
Cis isomer (D111a): ¹ HNMR δ (DMSO, 500 MHz): 0.868 (6H, m), 1.392 (2H, m broad), 1.478 (8H, m), 1.739 (2H, m), 1.992 (2H, d), 2.294 (5H, m), 2.821 (2H, d), 3.300 (2H below water peak), 3.359 (1H, s broad), 3.646 (1H, s broad), 6.504 (1H, d), 6.932 ( 1H, s), 7.954 (1H, d), 8.023 (1H, d)
Trans isomer (D111b): ¹ HNMR δ (DMSO, 500 MHz): 0.849 (6H, m), 1.107 (2H, t), 1.499 (8H, m), 1.869 (2H, d), 1.993 (2H, d ), 2.886 (5H, m), 2.790 (2H, d), 3.197 (1H, m), 3.315 (2H below the water peak), 3.652 (1H, m broad), 6.505 (1H, d), 6.936 (1H, s), 7.957 (1H, d), 8.040 (1H, d)

（Ｄ１１２）
Ｎ−（５−メチル−２−ニトロフェニル）−１−［シス−１−メチル−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ１１１ａ、５７ｍｇ、０．１４７ｍｍｏｌ）をＥｔＯＨ（５ｍｌ）に溶解し、室温にて、ラネーニッケル（５０％水性懸濁液０．２ｍｌ）を加えた。この混合物を６０℃まで加熱し、ヒドラジン水和物（１０当量、１．４７ｍｍｏｌ、０．０４６ｍｌ）を６０℃で滴下した。この反応物を６０℃で４時間攪拌した。この混合物を室温まで冷却し、セライトで濾過した。次に、溶媒を蒸発させ、標題化合物を得た（５３ｍｇ、完全に変換）。Ｍ^＋＋Ｈ＝３６０
¹HNMR δ(DMSO, 400 MHz): 0.861 (6H, m), 1.413 (10H, m), 1.723 (2H, dd), 1.939 (2H, d), 2.100 (3H, s), 2.151 (2H, t), 2.881 (2H, d), 3.177 (1H, s ブロード), 3.306 (ウォーターピーク下nH), 4.043 (1H, d), 4.253 (1H, s ブロード), 6.178 (1H, d), 6.263, (1H, s), 6.413 (1H, d) Description 112. (2-Amino-5-methylphenyl) {1- [cis-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinyl} amine (D112)

(D112)
N- (5-methyl-2-nitrophenyl) -1- [cis-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinamine (D111a, 57 mg, 0.147 mmol) in EtOH (5 ml) Dissolve and at room temperature Raney nickel (0.2 ml of 50% aqueous suspension) was added. The mixture was heated to 60 ° C. and hydrazine hydrate (10 eq, 1.47 mmol, 0.046 ml) was added dropwise at 60 ° C. The reaction was stirred at 60 ° C. for 4 hours. The mixture was cooled to room temperature and filtered through celite. The solvent was then evaporated to give the title compound (53 mg, complete conversion). M ⁺ + H = 360
¹ HNMR δ (DMSO, 400 MHz): 0.861 (6H, m), 1.413 (10H, m), 1.723 (2H, dd), 1.939 (2H, d), 2.100 (3H, s), 2.151 (2H, t ), 2.881 (2H, d), 3.177 (1H, s broad), 3.306 (nH under water peak), 4.043 (1H, d), 4.253 (1H, s broad), 6.178 (1H, d), 6.263, ( 1H, s), 6.413 (1H, d)

（Ｄ１１３）
Ｎ−（５−メチル−２−ニトロフェニル）−１−［トランス−１−メチル−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ１１１ｂ、４９ｍｇ、０．１２６ｍｍｏｌ）をＥｔＯＨ（５ｍｌ）に溶解し、室温にて、ラネーニッケル（５０％水性懸濁液０．２ｍｌ）を加えた。この混合物を６０℃まで加熱し、ヒドラジン水和物（１０当量、１．２６ｍｍｏｌ、０．０３９ｍｌ）を６０℃で滴下した。この反応物を６０℃で４時間攪拌した。この混合物を室温まで冷却し、セライトで濾過した。次に、溶媒を蒸発させ、標題化合物を得た（４５ｍｇ、完全に変換）。Ｍ^＋＋Ｈ＝３６０
¹HNMR δ(DMSO, 400 MHz): 0.841 (6H, m), 1.086 (2H, t), 1.335 (2H, q), 1.481 (6H, m), 1.871 (2H, d), 1.942 (2H, d), 2.121 (5H, m), 2.855 (2H, d), 3.186 (2H, m ブロード), 3.326 (ウォーターピーク下2H), 4.074 (1H, d), 4.258 (1H, s ブロード), 6.177 (1H, d), 6.268 (1H, s), 6.412 (1H, d) Description 113. (2-Amino-5-methylphenyl) {1- [trans-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinyl} amine (D113)

(D113)
N- (5-methyl-2-nitrophenyl) -1- [trans-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidineamine (D111b, 49 mg, 0.126 mmol) in EtOH (5 ml). Dissolve and at room temperature Raney nickel (0.2 ml of 50% aqueous suspension) was added. The mixture was heated to 60 ° C. and hydrazine hydrate (10 eq, 1.26 mmol, 0.039 ml) was added dropwise at 60 ° C. The reaction was stirred at 60 ° C. for 4 hours. The mixture was cooled to room temperature and filtered through celite. The solvent was then evaporated to give the title compound (45 mg, complete conversion). M ⁺ + H = 360
¹ HNMR δ (DMSO, 400 MHz): 0.841 (6H, m), 1.086 (2H, t), 1.335 (2H, q), 1.481 (6H, m), 1.871 (2H, d), 1.942 (2H, d ), 2.121 (5H, m), 2.855 (2H, d), 3.186 (2H, m broad), 3.326 (2H below water peak), 4.074 (1H, d), 4.258 (1H, s broad), 6.177 (1H , d), 6.268 (1H, s), 6.412 (1H, d)

（Ｄ１１４）
０℃にて、ＴＨＦ（１５０ｍｌ）中、ジイソプロピルアミン（５．７ｍｌ、４０ｍｍｏｌ）の溶液に、ｎ−ブチルリチウム（ヘキサン中２．５Ｍ １６ｍｌ、４０ｍｍｏｌ）を加えた。０℃でさらに１０分後、これを−７０℃まで冷却し、テトラヒドロフラン（３０ｍｌ）中、４−（ｔｅｒｔ−ブチルジメチルシリルオキシ）シクロヘキサンカルボン酸エチル（Ｄ５０、８．６ｇ）を加えた。−７０℃で１時間後、ヨードエタン（７．２ｍｌ）を加え、この溶液を室温まで温めた。室温で２時間後、これを塩化アンモニウム水溶液／酢酸エチルで分液し、有機層を乾燥させ、蒸発させ、クロマトグラフィー（５０ｇシリカ、ヘキサン中０〜１０％酢酸エチル）により精製し、標題化合物を得た（６．２ｇ）。 Description 114.1-Ethyl-4- (tert-butyldimethylsilyloxy) -cyclohexanecarboxylate cis-ethyl (D114)

(D114)
To a solution of diisopropylamine (5.7 ml, 40 mmol) in THF (150 ml) at 0 ° C. was added n-butyllithium (2.5 M in hexane 16 ml, 40 mmol). After an additional 10 minutes at 0 ° C., it was cooled to −70 ° C. and ethyl 4- (tert-butyldimethylsilyloxy) cyclohexanecarboxylate (D50, 8.6 g) was added in tetrahydrofuran (30 ml). After 1 hour at −70 ° C., iodoethane (7.2 ml) was added and the solution was allowed to warm to room temperature. After 2 hours at room temperature, it was partitioned between aqueous ammonium chloride / ethyl acetate, the organic layer was dried, evaporated and purified by chromatography (50 g silica, 0-10% ethyl acetate in hexane) to give the title compound. Obtained (6.2 g).

（Ｄ１１５）
１−エチル−４−（ｔｅｒｔ−ブチルジメチルシリルオキシ）−シクロヘキサンカルボン酸シス−エチル（Ｄ１１４、６．２ｇ、２０ｍｍｏｌ）およびフッ化テトラブチルアンモニウム（テトラヒドロフラン中１Ｍ ２５ｍｌ、２５ｍｍｏｌ）の混合物を１８時間室温で攪拌した後、クエン酸水溶液／ジエチルエーテルで分液し、有機層を乾燥させ、蒸発させ、クロマトグラフィー（２０ｇシリカ、ヘキサン中０〜５０％酢酸エチル）により精製し、標題化合物を得た（４．０ｇ）。 Description 115.1-Ethyl-4-hydroxycyclohexanecarboxylic acid cis-ethyl (D115)

(D115)
A mixture of 1-ethyl-4- (tert-butyldimethylsilyloxy) -cyclohexanecarboxylate cis-ethyl (D114, 6.2 g, 20 mmol) and tetrabutylammonium fluoride (1M in tetrahydrofuran, 25 ml, 25 mmol) was stirred at room temperature for 18 hours. The mixture was partitioned between aqueous citric acid / diethyl ether and the organic layer was dried, evaporated and purified by chromatography (20 g silica, 0-50% ethyl acetate in hexane) to give the title compound ( 4.0 g).

（Ｄ１１６）
０℃にて、１−エチル−４−ヒドロキシシクロヘキサンカルボン酸シス−エチル（Ｄ１１５、４．０ｇ、２０ｍｍｏｌ）、トリフェニルホスフィン（６．５ｇ、２５ｍｍｏｌ）、クロロ酢酸（２．４ｇ、２５ｍｍｏｌ）およびＴＨＦ（１００ｍｌ）の混合物にアゾジカルボン酸ジイソプロピル（５．０ｍｌ、２５ｍｍｏｌ）を滴下した。室温でさらに７６時間後、この溶液を蒸発させ、クロマトグラフィー（５０ｇシリカ、ヘキサン中１０〜５０％酢酸エチル）により精製し、標題化合物を得た（３．０ｇ）。 Description 116.1-Ethyl-4- (chloroacetoxy) cyclohexanecarboxylic acid trans-ethyl (D116)

(D116)
At 0 ° C., cis-ethyl 1-ethyl-4-hydroxycyclohexanecarboxylate (D115, 4.0 g, 20 mmol), triphenylphosphine (6.5 g, 25 mmol), chloroacetic acid (2.4 g, 25 mmol) and THF To a mixture of (100 ml), diisopropyl azodicarboxylate (5.0 ml, 25 mmol) was added dropwise. After an additional 76 hours at room temperature, the solution was evaporated and purified by chromatography (50 g silica, 10-50% ethyl acetate in hexanes) to give the title compound (3.0 g).

（Ｄ１１７）
メタノール（５０ｍｌ）中、１−エチル−４−（クロロアセトキシ）−シクロヘキサンカルボン酸トランス−エチル（Ｄ１１６、３．０ｇ、１２ｍｍｏｌ）の混合物および炭酸カリウム（１．７ｇ、１２ｍｍｏｌ）を室温で１時間攪拌した後、塩化アンモニウム水溶液／酢酸エチルで分液し、有機層を乾燥させ、蒸発させ、クロマトグラフィー（２０ｇシリカ、ヘキサン中０〜５０％酢酸エチル）により精製し、標題化合物を得た（１．５ｇ）。 Description 117.1-Ethyl-4-hydroxycyclohexanecarboxylic acid trans-ethyl (D117)

(D117)
A mixture of 1-ethyl-4- (chloroacetoxy) -cyclohexanecarboxylate trans-ethyl (D116, 3.0 g, 12 mmol) and potassium carbonate (1.7 g, 12 mmol) in methanol (50 ml) was stirred at room temperature for 1 hour. After partitioning with aqueous ammonium chloride / ethyl acetate, the organic layer was dried, evaporated and purified by chromatography (20 g silica, 0-50% ethyl acetate in hexane) to give the title compound (1. 5g).

（Ｄ１１８）
１−エチル−４−ヒドロキシシクロヘキサンカルボン酸トランス−エチル（Ｄ１１７、１．５ｇ、７．５ｍｍｏｌ）、塩化ｔｅｒｔ−ブチルジメチルシリル（１．２ｇ、８．０ｍｍｏｌ）、イミダゾール（１．１ｇ、１６．０ｍｍｏｌ）およびジメチルホルムアミド（１０ｍｌ）の混合物を一晩室温で攪拌した後、水／酢酸エチルで分液し、有機層を乾燥させ、蒸発させ、クロマトグラフィー（２０ｇシリカ、ヘキサン中０〜１０％酢酸エチル）により精製し、標題化合物を得た（１．８ｇ）。 Description 118.1-Ethyl-4- (tert-butyldimethylsilyloxy) -cyclohexanecarboxylate trans-ethyl (D118)

(D118)
1-ethyl-4-hydroxycyclohexanecarboxylic acid trans-ethyl (D117, 1.5 g, 7.5 mmol), tert-butyldimethylsilyl chloride (1.2 g, 8.0 mmol), imidazole (1.1 g, 16.0 mmol) ) And dimethylformamide (10 ml) were stirred overnight at room temperature, then partitioned with water / ethyl acetate, the organic layer was dried, evaporated and chromatographed (20 g silica, 0-10% ethyl acetate in hexanes). To give the title compound (1.8 g).

（Ｄ１１９）
０℃にて、１−エチル−４−（ｔｅｒｔ−ブチルジメチルシリルオキシ）−シクロヘキサンカルボン酸トランス−エチル（Ｄ１１８、１．８ｇ、６．０ｍｍｏｌ）、トリエチルシラン（１．３ｍｌ、８．０ｍｍｏｌ）、三臭化ビスマス（０．３ｇ、０．６ｍｍｏｌ）およびアセトニトリル（２５ｍｌ）の混合物にプロパナール（０．６ｍｌ、８．０ｍｍｏｌ）を加えた。この混合物を室温で３０分間攪拌した後、重炭酸ナトリウム水溶液／酢酸エチルで分液し、有機層を乾燥させ、蒸発させ、標題化合物をｔｅｒｔ−ブチルジメチルシリルトリエチルシロキサンとの１：１混合物として得た（２．７ｇ）。 Description 119.1-Ethyl-4-propoxycyclohexanecarboxylic acid trans-ethyl (D119)

(D119)
At 0 ° C., 1-ethyl-4- (tert-butyldimethylsilyloxy) -cyclohexanecarboxylic acid trans-ethyl (D118, 1.8 g, 6.0 mmol), triethylsilane (1.3 ml, 8.0 mmol), To a mixture of bismuth tribromide (0.3 g, 0.6 mmol) and acetonitrile (25 ml) was added propanal (0.6 ml, 8.0 mmol). The mixture was stirred at room temperature for 30 minutes, then partitioned between aqueous sodium bicarbonate / ethyl acetate, the organic layer was dried and evaporated to give the title compound as a 1: 1 mixture with tert-butyldimethylsilyltriethylsiloxane. (2.7 g).

（Ｄ１２０）
１−エチル−４−プロポキシシクロヘキサンカルボン酸トランス−エチル（Ｄ１１９、２．７ｇ、５．５ｍｍｏｌ）、メタノール（５０ｍｌ）、ＴＨＦ（５０ｍｌ）および１２．５Ｍ水酸化ナトリウム水溶液（４．０ｍｌ、５０ｍｍｏｌ）の混合物を一晩５０℃で攪拌した後、真空濃縮し、水／酢酸エチルで分液した。水層を酸性化し、ジエチルエーテルで抽出し、これを乾燥させ、蒸発させ、標題化合物を得た（４５０ｍｇ）。 Description 120. Trans-1-ethyl-4-propoxycyclohexanecarboxylic acid (D120)

(D120)
Of 1-ethyl-4-propoxycyclohexanecarboxylic acid trans-ethyl (D119, 2.7 g, 5.5 mmol), methanol (50 ml), THF (50 ml) and 12.5 M aqueous sodium hydroxide solution (4.0 ml, 50 mmol). The mixture was stirred overnight at 50 ° C., then concentrated in vacuo and partitioned between water / ethyl acetate. The aqueous layer was acidified and extracted with diethyl ether, which was dried and evaporated to give the title compound (450 mg).

（Ｄ１２１）
トランス−１−エチル−４−プロポキシシクロヘキサンカルボン酸（Ｄ１２０、４５０ｍｇ、２．１ｍｍｏｌ）、アジ化ジフェニルホスホリル（０．４ｍｌ、１．８ｍｍｏｌ）、トリエチルアミン（０．２７ｍｌ、０．２ｍｍｏｌ）およびトルエン（１０ｍｌ）の混合物を３０分間１００℃で加熱した後、冷却し、水で洗浄し、クロマトグラフィー（１０ｇシリカ、ヘキサン中０〜２０％酢酸エチル）により精製し、標題化合物を得た（２４０ｍｇ）。 Description 121. Trans-1-ethyl-4-propoxycyclohexyl isocyanate (D121)

(D121)
Trans-1-ethyl-4-propoxycyclohexanecarboxylic acid (D120, 450 mg, 2.1 mmol), diphenylphosphoryl azide (0.4 ml, 1.8 mmol), triethylamine (0.27 ml, 0.2 mmol) and toluene (10 ml) ) Was heated for 30 minutes at 100 ° C., then cooled, washed with water and purified by chromatography (10 g silica, 0-20% ethyl acetate in hexanes) to give the title compound (240 mg).

（Ｄ１２２）
トランス−１−エチル−４−プロポキシシクロヘキシルイソシアネート（Ｄ１２１、２４０ｍｇ、１．１ｍｍｏｌ）、ＴＨＦ（４ｍｌ）および５Ｍ塩酸水溶液（１ｍｌ、５．０ｍｍｏｌ）の混合物を室温で２時間攪拌した後、ＳＣＸ樹脂を用い、イオン交換クロマトグラフィーにより精製し、標題化合物を得た（９０ｍｇ）。 Description 122. Trans-1-ethyl-4-propoxycyclohexylamine (D122)

(D122)
After stirring a mixture of trans-1-ethyl-4-propoxycyclohexyl isocyanate (D121, 240 mg, 1.1 mmol), THF (4 ml) and 5M aqueous hydrochloric acid (1 ml, 5.0 mmol) at room temperature for 2 hours, the SCX resin was added. And purified by ion exchange chromatography to give the title compound (90 mg).

（Ｄ１２３）
トランス−１−エチル−４−プロポキシシクロヘキシルアミン（Ｄ１２２、９０ｍｇ、０．５ｍｍｏｌ）、１−エチル−１−メチル−４−オキソピペリジニウムヨージド（Ｄ４４、２１０ｍｇ、０．８ｍｍｏｌ）、炭酸カリウム（１０ｍｇ、０．０５ｍｍｏｌ）、水（２ｍｌ）およびエタノール（４ｍｌ）の混合物を８０℃で１時間加熱した後、冷却し、水／ジクロロメタンで分液し、クロマトグラフィー（１０ｇシリカ、０．２Ｍアンモニアを含有するジクロロメタン中０〜１０％メタノール）により精製し、標題化合物を得た（３０ｍｇ）。 Description 123. Trans-1- [4- (propoxy) -1-ethylcyclohexyl] -4-piperidone (D123)

(D123)
Trans-1-ethyl-4-propoxycyclohexylamine (D122, 90 mg, 0.5 mmol), 1-ethyl-1-methyl-4-oxopiperidinium iodide (D44, 210 mg, 0.8 mmol), potassium carbonate ( A mixture of 10 mg, 0.05 mmol), water (2 ml) and ethanol (4 ml) was heated at 80 ° C. for 1 hour, then cooled, partitioned between water / dichloromethane and chromatographed (10 g silica, 0.2 M ammonia). Containing 0-10% methanol in dichloromethane) to give the title compound (30 mg).

（Ｄ１２４）
トランス−１−［４−（プロポキシ）−１−エチルシクロヘキシル］−４−ピペリドン（Ｄ１２３、３０ｍｇ、０．１１ｍｍｏｌ）、メタノール中２Ｍアンモニア（２０ｍｌ、４０ｍｍｏｌ）および１０％パラジウム炭素ペースト（３０ｍｇ）の混合物を室温にて一晩、５０ｐｓｉで水素化した後、濾過し、蒸発させ、標題化合物を得た（３０ｍｇ）。 Description 124. Trans-1- [4- (propoxy) -1-ethylcyclohexyl] -4-piperidinamine (D124)

(D124)
A mixture of trans-1- [4- (propoxy) -1-ethylcyclohexyl] -4-piperidone (D123, 30 mg, 0.11 mmol), 2M ammonia in methanol (20 ml, 40 mmol) and 10% palladium on carbon paste (30 mg) Was hydrogenated at room temperature overnight at 50 psi, then filtered and evaporated to give the title compound (30 mg).

（Ｄ１２５）
室温にてアルゴン下、ジメチルホルムアミド（１ｍｌ）中、３−フルオロ−４−ニトロトルエン（３０ｍｇ、０．２０ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（０．１ｍｌ、０．６０ｍｍｏｌ）およびトランス−１−［４−（プロポキシ）−１−エチルシクロヘキシル］−４−ピペリジンアミン（Ｄ１２４、３０ｍｇ、０．１１ｍｍｏｌ）で処理し、８０℃で１８時間加熱した。冷却反応物を酢酸エチルで希釈し、水で３回洗浄した後、乾燥させ、蒸発させ、クロマトグラフィーに付し（５ｇシリカ、０．２Ｍアンモニアを含有するジクロロメタン中０〜５％メタノール）、標題化合物を得た（４０ｍｇ）。 Description 125. Trans-N- (5-methyl-2-nitrophenyl) -1- (1-ethyl-4-propoxycyclohexyl) -4-piperidineamine (D125)

(D125)
A stirred solution of 3-fluoro-4-nitrotoluene (30 mg, 0.20 mmol) in dimethylformamide (1 ml) under argon at room temperature was diluted with diisopropylethylamine (0.1 ml, 0.60 mmol) and trans-1- [4- Treated with (propoxy) -1-ethylcyclohexyl] -4-piperidineamine (D124, 30 mg, 0.11 mmol) and heated at 80 ° C. for 18 hours. The cooled reaction was diluted with ethyl acetate and washed 3 times with water, then dried, evaporated and chromatographed (5 g silica, 0-5% methanol in dichloromethane containing 0.2 M ammonia). Compound was obtained (40 mg).

（Ｄ１２６）
５０℃にて、エタノール（５ｍｌ）中、トランス−Ｎ−（５−メチル−２−ニトロフェニル）−１−（１−エチル−４−プロポキシシクロヘキシル）−４−ピペリジンアミン（Ｄ１２５、４０ｍｇ、０．１０ｍｍｏｌ）の攪拌懸濁液をラネーニッケル（１０％水性懸濁液０．５ｍｌ）、次いでヒドラジン水和物（０．１ｍｌ、２．０ｍｍｏｌ）で処理した。この混合物を同じ温度で１時間加熱した後、セライトで濾過し、濾液を蒸発させ、トルエン、次いでジエチルエーテルから再蒸発させ、標題化合物を得た（４０ｍｇ）。 Description 126. Trans-5-methyl-N- [1- (1-ethyl-4-propoxycyclohexyl) -4-piperidinyl] -1,2-benzenediamine (D126)

(D126)
Trans-N- (5-methyl-2-nitrophenyl) -1- (1-ethyl-4-propoxycyclohexyl) -4-piperidinamine (D125, 40 mg, 0.4 mg in ethanol (5 ml) at 50 ° C. A stirred suspension of 10 mmol) was treated with Raney nickel (10 ml aqueous suspension 0.5 ml) followed by hydrazine hydrate (0.1 ml, 2.0 mmol). The mixture was heated at the same temperature for 1 hour, then filtered through celite, the filtrate was evaporated and re-evaporated from toluene then diethyl ether to give the title compound (40 mg).

（Ｄ１２７）
室温にてアルゴン下、ジメチルホルムアミド（４ｍｌ）中、３−フルオロ−４−ニトロベンゾニトリル（１３３ｍｇ、０．８０ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（０．４６ｍｌ、２．６ｍｍｏｌ）、次いで１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ１２、２２５ｍｇ、０．７５ｍｍｏｌ）で処理し、７０℃で６時間加熱した。この溶液を真空濃縮し、残渣を１０％Ｎａ_２ＣＯ_３溶液（１０ｍｌ）で処理し、ジクロロメタンで抽出した（２×１５ｍｌ）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、残った固体を０〜１０％メタノール／ジクロロメタンで溶出するシリカゲル（５ｇ）でのクロマトグラフィーに付して橙色固体を得、これをＭｅＯＨ（８ｍｌ）から再結晶させ、標題化合物を橙色固体として得た（１７５ｍｇ、６３％）。ＭＨ^＋３７３
¹H NMR δ(CDCl₃, 400 MHz): 1-18-1.40 (4H, m), 1.21 (3H, t), 1.60-1.72 (2H, m), 1.90-1.98 (2H, m), 2.03-2.18 (4H, m), 2.32-2.50 (3H, m), 2.88-2.98 (2H, m), 3.13-3.23 (1H, m), 3.42-3.58 (3H, q + m), 6.84 (1H, dd), 7.15 (1H, d), 8.08 (1H, d), 8.25 (1H, d) Description 127.3-({1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} amino) -4-nitrobenzonitrile (D127)

(D127)
A stirred solution of 3-fluoro-4-nitrobenzonitrile (133 mg, 0.80 mmol) in dimethylformamide (4 ml) under argon at room temperature was diluted with diisopropylethylamine (0.46 ml, 2.6 mmol) and then 1- [trans Treated with -4- (ethyloxy) cyclohexyl] -4-piperidineamine dihydrochloride (D12, 225 mg, 0.75 mmol) and heated at 70 ° C. for 6 hours. The solution was concentrated in vacuo and the residue was treated with 10% Na ₂ CO ₃ solution (10 ml) and extracted with dichloromethane (2 × 15 ml). The combined extracts were dried (Na ₂ SO ₄ ), concentrated in vacuo, and the remaining solid was chromatographed on silica gel (5 g) eluting with 0-10% methanol / dichloromethane to give an orange solid, which Was recrystallized from MeOH (8 ml) to give the title compound as an orange solid (175 mg, 63%). MH ⁺ 373
¹ H NMR δ (CDCl ₃ , 400 MHz): 1-18-1.40 (4H, m), 1.21 (3H, t), 1.60-1.72 (2H, m), 1.90-1.98 (2H, m), 2.03- 2.18 (4H, m), 2.32-2.50 (3H, m), 2.88-2.98 (2H, m), 3.13-3.23 (1H, m), 3.42-3.58 (3H, q + m), 6.84 (1H, dd ), 7.15 (1H, d), 8.08 (1H, d), 8.25 (1H, d)

（Ｄ１２８）
室温にてアルゴン下、エタノール（８ｍｌ）および水（２ｍｌ）中、３−（｛１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝アミノ）−４−ニトロベンゾニトリル（Ｄ１２７、１４５ｍｇ、０．３９ｍｍｏｌ）の攪拌懸濁液を鉄粉（２２０ｍｇ）、次いで濃ＨＣｌ（０．２ｍｌ）で処理し、１．５時間維持した。この混合物を真空濃縮し、残渣をＮａＨＣＯ_３溶液（１５ｍｌ）およびＥｔＯＡｃ（２０ｍｌ）で処理した後、よく振盪し、Ｋｉｅｓｅｌｇｕｈｒで濾過した。ＥｔＯＡｃ層を単離し、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、標題化合物を緑色／灰色固体を得（１２０ｍｇ、９０％）。ＭＨ^＋３４３。
¹H NMR δ(CDCl₃, 400MHz): 1.15-1.40 (7H, m), 1.42-1.55 (2H, m), 1.80-1.98 (H, mと仮定), 2.00-2.20 (4H, mと仮定), 2.28-2.50 (3H, mと仮定), 2.85-2.95 (2H, m), 3.00-3.30 (3H, m), 3.51 (2H, q), 3.78 (2H, s), 6.69 (1H, d), 6.85 (1H, d), 6.99 (1H, dd) Description 128.4-Amino-3-({1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} amino) benzonitrile (D128)

(D128)
3-({1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} amino) -4-nitrobenzonitrile (D127, 145 mg) in ethanol (8 ml) and water (2 ml) under argon at room temperature. , 0.39 mmol) was treated with iron powder (220 mg) followed by concentrated HCl (0.2 ml) and maintained for 1.5 hours. The mixture was concentrated in vacuo and the residue was treated with NaHCO ₃ solution (15 ml) and EtOAc (20 ml), then shaken well and filtered through Kieselguhr. The EtOAc layer was isolated, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a green / grey solid (120 mg, 90%). MH ⁺ 343.
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.15-1.40 (7H, m), 1.42-1.55 (2H, m), 1.80-1.98 (assuming H, m), 2.00-2.20 (assuming 4H, m) , 2.28-2.50 (assuming 3H, m), 2.85-2.95 (2H, m), 3.00-3.30 (3H, m), 3.51 (2H, q), 3.78 (2H, s), 6.69 (1H, d) , 6.85 (1H, d), 6.99 (1H, dd)

（Ｄ１２９）
アルゴン下、ジメチルホルムアミド（３ｍｌ）中、３−フルオロ−４−ニトロベンゾニトリル（１１１ｍｇ、０．６７ｍｍｏｌ）および１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ５８、２００ｍｇ、０．６１ｍｍｏｌ）の溶液をジイソプロピルエチルアミン（０．３ｍｌ、１．３８ｍｍｏｌ）で処理し、反応混合物をマイクロ波反応装置にて１１０℃で２０分間加熱した。次に、得られた混合物を真空濃縮し、残渣をＮａＨＣＯ_３水溶液（３０ｍｌ）で処理した後、酢酸エチルで抽出した（２×４０ｍｌ）。合わせた抽出液を乾燥させ（ＭｇＳＯ_４）、真空濃縮し、粗材料を橙色残渣として得た。次に、残渣を０〜１０％メタノール／ジクロロメタンで溶出するシリカでのクロマトグラフィーに付し、標題化合物（２００ｍｇ、８０％）を橙色油状物として得た。Ｍ^＋＋Ｈ＝３８７ Description 129.3-({1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} amino) -4-nitrobenzonitrile (D129)

(D129)
3-Fluoro-4-nitrobenzonitrile (111 mg, 0.67 mmol) and 1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidineamine dihydrochloride in dimethylformamide (3 ml) under argon A solution of the salt (D58, 200 mg, 0.61 mmol) was treated with diisopropylethylamine (0.3 ml, 1.38 mmol) and the reaction mixture was heated in a microwave reactor at 110 ° C. for 20 minutes. The resulting mixture was then concentrated in vacuo and the residue was treated with aqueous NaHCO ₃ (30 ml) and extracted with ethyl acetate (2 × 40 ml). The combined extracts were dried (MgSO ₄ ) and concentrated in vacuo to give the crude material as an orange residue. The residue was then chromatographed on silica eluting with 0-10% methanol / dichloromethane to give the title compound (200 mg, 80%) as an orange oil. M ⁺ + H = 387

（Ｄ１３０）
室温にてアルゴン下、エタノール／水（１０ｍｌ／２ｍｌ）中、３−（｛１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジニル｝アミノ）−４−ニトロベンゾニトリル（１１０ｍｇ、０．２８５ｍｍｏｌ）の攪拌溶液を鉄粉（２５０ｍｇ）、次いで濃ＨＣｌ（０．３ｍｌ）で処理し、反応混合物を３０分間維持した。次に、この均質な混合物を真空濃縮し、得られた残渣をＮａＨＣＯ_３水溶液（５０ｍｌ）および酢酸エチル（５０ｍｌ）で処理した。次に、この二相混合物をよく振盪した後、Ｋｉｅｓｅｌｇｕｈｒで濾過し、有機相を分離し、乾燥させ（ＭｇＳＯ_４）、揮発性成分を真空蒸発により除去し、粗生成物を得た（９０ｍｇ、ＮＭＲによれば５８％）。Ｍ^＋＋Ｈ＝３５７ Description 130.4-amino-3-({1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} amino) benzonitrile (D130)

(D130)
3-({1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} amino) -4-nitrobenzonitrile in ethanol / water (10 ml / 2 ml) under argon at room temperature. A stirred solution of 110 mg, 0.285 mmol) was treated with iron powder (250 mg) followed by concentrated HCl (0.3 ml) and the reaction mixture was maintained for 30 minutes. The homogeneous mixture was then concentrated in vacuo and the resulting residue was treated with aqueous NaHCO ₃ (50 ml) and ethyl acetate (50 ml). The biphasic mixture was then shaken well and then filtered through Kieselguhr, the organic phase was separated and dried (MgSO ₄ ) and the volatile components were removed by vacuum evaporation to give the crude product (90 mg, 58% according to NMR). M ⁺ + H = 357

（Ｄ１３１）
氷浴温度にてアルゴン下、Ｎ−メチルピロリジノン（２５ｍｌ）中、１，４−ジオキサスピロ［４．５］デカン−８−オール（Ｄ１、５．０ｇ）、臭化プロパルギル（４．６ｇ）の攪拌溶液を水素化ナトリウム（６０％油分散物２．６ｇ）で少量ずつ処理した後、この混合物を一晩室温まで温めた。該混合物を水で処理し、この混合物をヘキサン−酢酸エチル−エーテルの混合液で抽出した。有機抽出液を重炭酸ナトリウムで洗浄した後、乾燥させ（Ｎａ_２ＳＯ_４）、溶媒を除去し、残渣をヘキサン／酢酸エチル１０〜３０％で溶出するシリカゲルでのクロマトグラフィーに付し、標題化合物を油状物として得た（３．１１ｇ）。
¹HNMR δ(CDCl₃, 400 MHz): 1.55 (2H, m), 1.7-1.9 (6H, m), 2.41 (1H, m), 3.55 (1H, m), 3.92 (4H, m), 4.17 (2H, m) Description 131.8- (2-propyn-1-yloxy) -1,4-dioxaspiro [4.5] decane (D131)

(D131)
Stirring of 1,4-dioxaspiro [4.5] decan-8-ol (D1, 5.0 g) and propargyl bromide (4.6 g) in N-methylpyrrolidinone (25 ml) under argon at ice bath temperature After the solution was treated in portions with sodium hydride (2.6 g of 60% oil dispersion), the mixture was allowed to warm to room temperature overnight. The mixture was treated with water and the mixture was extracted with a mixture of hexane-ethyl acetate-ether. The organic extract is washed with sodium bicarbonate and then dried (Na ₂ SO ₄ ), the solvent is removed, and the residue is chromatographed on silica gel eluting with 10-30% hexane / ethyl acetate to give the title compound. As an oil (3.11 g).
¹ HNMR δ (CDCl ₃ , 400 MHz): 1.55 (2H, m), 1.7-1.9 (6H, m), 2.41 (1H, m), 3.55 (1H, m), 3.92 (4H, m), 4.17 ( 2H, m)

（Ｄ１３２）
テトラヒドロフラン（５ｍｌ）中、８−（２−プロピン−１−イルオキシ）−１，４−ジオキサスピロ［４．５］デカン（Ｄ１３１、３．１ｇ）の溶液を５Ｍ ＨＣｌ（２０ｍｌ）で処理し、２時間攪拌した。得られた混合物を水で希釈し、ジクロロメタンで抽出した（２回）。合わせた抽出液をブラインで洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、標題化合物を油状物として得た（２．３７ｇ）。
¹H NMR δ(CDCl₃, 400 MHz): 2.00 (2H, m), 2.12 (2H, m), 2.3 (2H, m), 2.46 (1H, m) 2.6 (2H, m), 3.96 (1H, m), 4.25 (2H, s) Description 132.4- (2-Propin-1-yloxy) cyclohexanone (D132)

(D132)
A solution of 8- (2-propyn-1-yloxy) -1,4-dioxaspiro [4.5] decane (D131, 3.1 g) in tetrahydrofuran (5 ml) was treated with 5M HCl (20 ml) for 2 hours. Stir. The resulting mixture was diluted with water and extracted with dichloromethane (twice). The combined extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as an oil (2.37 g).
¹ H NMR δ (CDCl ₃ , 400 MHz): 2.00 (2H, m), 2.12 (2H, m), 2.3 (2H, m), 2.46 (1H, m) 2.6 (2H, m), 3.96 (1H, m), 4.25 (2H, s)

（Ｄ１３３）
アルゴン下、１，２−ジクロロエタン（５０ｍｌ）中、４−（２−プロピン−１−イルオキシ）シクロヘキサノン（Ｄ１３２、１ｇ）の攪拌溶液を４−ピペリジニルカルバミン酸１，１−ジメチルエチル（１．４ｇ）、トリアセトキシ水素化ホウ素ナトリウム（２．０ｇ）で処理した後、得られた混合物を室温で２時間攪拌した。反応混合物をジクロロメタンで希釈した後、Ｎａ_２ＣＯ_３溶液、ブラインで洗浄した後、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。粗生成物をＢｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカカラムでのクロマトグラフィー（酢酸エチル／ｎ−ヘキサン）により精製し、シスおよびトランス異性体の混合物として得た（１．１ｇ）。ＭＨ^＋＝３３７ Description 133. {1- [4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinyl} carbamic acid cis / trans-1,1-dimethylethyl (D133)

(D133)
Under argon, a stirred solution of 4- (2-propyn-1-yloxy) cyclohexanone (D132, 1 g) in 1,2-dichloroethane (50 ml) was added to 1,1-dimethylethyl 4-piperidinylcarbamate (1. 4 g), after treatment with sodium triacetoxyborohydride (2.0 g), the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and then washed with Na ₂ CO ₃ solution, brine, then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by chromatography on a Biotage KP-NH ™ -silica column (ethyl acetate / n-hexane) and obtained as a mixture of cis and trans isomers (1.1 g). MH ⁺ = 337

（Ｄ１３４）
｛１−［４−（２−プロピン−１−イルオキシ）シクロヘキシル］−４−ピペリジニル｝カルバミン酸シス／トランス−１，１−ジメチルエチル（Ｄ１３３、１．１ｇ）を、塩化水素で飽和させたエタノール溶液（２５ｍｌ）中で２時間攪拌した。溶媒を蒸発させ、標題化合物を白色固体として得た（１．２７ｇ）。Ｍ^＋＋Ｈ＝２５３ Description 134. Cis / trans-1- [4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidineamine dihydrochloride (D134)

(D134)
Ethanol saturated with {1- [4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinyl} carbamate cis / trans-1,1-dimethylethyl (D133, 1.1 g) with hydrogen chloride Stir in solution (25 ml) for 2 hours. The solvent was evaporated to give the title compound as a white solid (1.27g). M ⁺ + H = 253

乾燥ジメチルホルムアミド（３ｍｌ）中、シス／トランス−１−［４−（２−プロピン−１−イルオキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ１３４、０．２０ｇ）、ジイソプロピルエチルアミン（１ｍｌ）および３−フルオロ−４−ニトロトルエン（０．２ｇ）の溶液をマイクロ波反応装置にて２００℃で２０分間加熱した。次に、この粗混合物を室温まで冷却し、溶媒を蒸発させ、残渣をＳＣＸカートリッジに乗せた。このカートリッジをメタノール、次いで２Ｍメタノール性アンモニアで溶出した。メタノール性アンモニア画分を蒸発させ、粗生成物を得た。上記を数回繰り返した。酢酸エチル／ｎ−ヘキサン勾配を用い、Ｂｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカでのクロマトグラフィーを繰り返すことで標題化合物のシスおよびトランス異性体の分離を得た。 Description 135. N- (5-methyl-2-nitrophenyl) -1- [trans-4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinamine (D135a) and N- (5-methyl-2-nitro Phenyl) -1- [cis-4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinamine (D135b)

Cis / trans-1- [4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidineamine dihydrochloride (D134, 0.20 g), diisopropylethylamine (1 ml) and in dry dimethylformamide (3 ml) A solution of 3-fluoro-4-nitrotoluene (0.2 g) was heated in a microwave reactor at 200 ° C. for 20 minutes. The crude mixture was then cooled to room temperature, the solvent was evaporated, and the residue was loaded on an SCX cartridge. The cartridge was eluted with methanol followed by 2M methanolic ammonia. The methanolic ammonia fraction was evaporated to give the crude product. The above was repeated several times. Repeated chromatography on Biotage KP-NH ™ -Silica using an ethyl acetate / n-hexane gradient provided separation of the cis and trans isomers of the title compound.

An early eluting isomer (cis isomer; D135b) was obtained as a yellow solid. MH ⁺ = 372
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.94 (2H, m), 1.05-1.25 (obs, m), 1.95-2.14 (4H, m), 1.55-1.70 (obs, m), 2.33 (3H, t), 2.35-2.55 (4H, m), 2.88 (2H, m), 3.15 (1H, m), 3.22 (1H, m), 4.14 (2H, m), 3.52 (2H, m), 6.14 (1H , d), 6.61 (1H, s) 8.04 (1H, d), 8.19 (1H, d)

The slow eluting isomer (trans isomer; D135a) was obtained as a white solid. MH ⁺ = 372
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.2-1.4 (4H, m), 1.65 (2H, m), 1.95 (2H, m), 2.05-2.18 (4H, m), 2.33 (3H, t) , 2.35-2.5 (4H, m), 2.88 (2H, m), 3.42 (1H, m), 2.55 (1H, m), 4.19 (2H, m), 6.42 (1H, d), 6.61 (1H, s ) 8.07 (1H, d), 8.2 (1H, d)

（Ｄ１３６）
６０で攪拌した濃塩酸（５ｍｌ）中、塩化スズ（ＩＩ）（０．４５ｇ）の溶液に、エタノール（７ｍｌ）中、Ｎ−（４−フルオロ−５−メチル−２−ニトロフェニル）−１−［シス−１−メチル−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ１３５ｂ、０．１８ｍｇ）の溶液を１０分かけて加えた。この混合物を６０℃で０．５時間加熱した後、希水酸化ナトリウム溶液とジクロロメタンの混合物中に注いだ。ジクロロメタン層を分離し、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、溶媒を除去し、標題化合物を油状物として得た（０．２ｇ）。ＭＨ^＋＝３４２ Wherein 136.4- methyl ^-N 2 - {1- [cis-4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D 136)

(D136)
To a solution of tin (II) chloride (0.45 g) in concentrated hydrochloric acid (5 ml) stirred at 60, N- (4-fluoro-5-methyl-2-nitrophenyl) -1-in ethanol (7 ml) was added. A solution of [cis-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinamine (D135b, 0.18 mg) was added over 10 minutes. The mixture was heated at 60 ° C. for 0.5 hour and then poured into a mixture of dilute sodium hydroxide solution and dichloromethane. The dichloromethane layer was separated, washed with brine, dried over sodium sulfate and the solvent removed to give the title compound as an oil (0.2g). MH ⁺ = 342

（Ｄ１３７）
６０℃で攪拌した濃塩酸（８ｍｌ）中、塩化スズ（ＩＩ）（０．８ｇ）の溶液に、エタノール（１５ｍｌ）中、Ｎ−（４−フルオロ−５−メチル−２−ニトロフェニル）−１−［トランス−１−メチル−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ１３５ａ、０．２６９ｍｇ）の溶液を５分かけて加えた。この混合物を６０℃で０．５時間加熱した後、希水酸化ナトリウム溶液とジクロロメタンの混合物中に注いだ。ジクロロメタン層を分離し、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、溶媒を除去し、標題化合物をガラスとして得た（０．２８ｇ）。ＭＨ^＋＝３４２ Wherein 137.4- methyl ^-N 2 - {1- [trans-4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D137)

(D137)
To a solution of tin (II) chloride (0.8 g) in concentrated hydrochloric acid (8 ml) stirred at 60 ° C. was added N- (4-fluoro-5-methyl-2-nitrophenyl) -1 in ethanol (15 ml). A solution of [trans-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinamine (D135a, 0.269 mg) was added over 5 minutes. The mixture was heated at 60 ° C. for 0.5 hour and then poured into a mixture of dilute sodium hydroxide solution and dichloromethane. The dichloromethane layer was separated, washed with brine, dried over sodium sulfate and the solvent removed to give the title compound as a glass (0.28g). MH ⁺ = 342

（Ｄ１３８）
ジメチルホルムアミド（２００ｍＬ）中、三フッ化３−クロロ−４−ニトロベンゾ（１９．０ｇ、８４ｍｍｏｌ）、炭酸ナトリウム（８．９ｇ、８４ｍｍｏｌ）およびヨウ化カリウム（０．１４ｇ、０．８４ｍｍｏｌ）の攪拌懸濁液に、エチル−４−アミノ−１−ピペリジン−カルボキシレート（１６．０ｇ、９２ｍｍｏｌ）を加えた。この混合物を９０℃まで加熱し、１５時間攪拌した後、冷却した。この反応混合物を水（２００ｍｌ）および酢酸エチル（２００ｍｌ）で希釈した。水相を分離し、有機相を水で抽出した（２×２００ｍｌ）。有機相をＭｇＳＯ_４で乾燥させ、減圧下で蒸発させた。残渣を酢酸エチル／ヘキサン（１：５）で溶出するシリカでのカラムクロマトグラフィーにより精製し、標題化合物（１２．０ｇ、収率４０％）を橙色固体として得た（Ｒ_ｆ：０．４（酢酸エチル／ヘキサン１：５））。 Description 138.4-{[2-Nitro-5- (trifluoromethyl) phenyl] amino} -1-piperidinecarboxylate (D138)

(D138)
Stirring of 3-chloro-4-nitrobenzo trifluoride (19.0 g, 84 mmol), sodium carbonate (8.9 g, 84 mmol) and potassium iodide (0.14 g, 0.84 mmol) in dimethylformamide (200 mL) To the suspension was added ethyl-4-amino-1-piperidine-carboxylate (16.0 g, 92 mmol). The mixture was heated to 90 ° C., stirred for 15 hours and then cooled. The reaction mixture was diluted with water (200 ml) and ethyl acetate (200 ml). The aqueous phase was separated and the organic phase was extracted with water (2 × 200 ml). The organic phase was dried over MgSO ₄ and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with ethyl acetate / hexane (1: 5) to give the title compound (12.0 g, 40% yield) as an orange solid (R _f : 0.4 ( Ethyl acetate / hexane 1: 5)).

（Ｄ１３９）
オートクレーブ（１０００ｍｌ）内で、メタノール（４００ｍｌ）中、４−｛［２−ニトロ−５−（トリフルオロメチル）フェニル］アミノ｝−１−ピペリジンカルボン酸エチル（Ｄ１３８、１８．０ｇ、５０ｍｍｏｌ）および５％Ｐｄ／Ｃ（１．７ｇ）の懸濁液を水素雰囲気下（〜３０気圧）に置いた。この混合物を室温で３時間攪拌した後、セライトパッドで濾過した。濾液を減圧下で濃縮して標題化合物（１５．９ｇ、収率９６％）を褐色固体として得、これをそれ以上精製せずに用いた（Ｒ_ｆ：０．３（酢酸エチル／ヘキサン７：８））。 Description 139.4-{[2-Amino-5- (trifluoromethyl) phenyl] amino} -1-piperidinecarboxylate (D139)

(D139)
Ethyl 4-{[2-nitro-5- (trifluoromethyl) phenyl] amino} -1-piperidinecarboxylate (D138, 18.0 g, 50 mmol) and 5 in methanol (400 ml) in an autoclave (1000 ml). A suspension of% Pd / C (1.7 g) was placed under a hydrogen atmosphere (˜30 atm). The mixture was stirred at room temperature for 3 hours and then filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (15.9 g, 96% yield) as a brown solid, which was used without further purification (R _f : 0.3 (ethyl acetate / hexane 7: 8)).

（Ｄ１４０）
アセトニトリル（２００ｍｌ）中、４−｛［２−アミノ−５−（トリフルオロメチル）フェニル］アミノ｝−１−ピペリジンカルボン酸エチル（Ｄ１３９、１２．７ｇ、３８ｍｍｏｌ）の攪拌溶液に、１，１’−カルボニルジイミダゾール（９．９ｇ、６１ｍｍｏｌ）を１０分かけて少量ずつ加えた。この反応混合物を室温で５時間攪拌した後、減圧下で溶媒を除去した。残渣をジクロロメタン（２００ｍｌ）で希釈し、１０％クエン酸水溶液で抽出した（２×１００ｍｌ）。有機相をＭｇＳＯ_４で乾燥させ、減圧下で蒸発させて標題化合物（１３．５ｇ、収率９９％）を褐色固体として得、これをそれ以上精製せずに用いた（Ｒ_ｆ：０．２（酢酸エチル））。 Description 140.4- [2-Oxo-6- (trifluoromethyl) -2,3-dihydro-1H-benzimidazol-1-yl] -1-piperidinecarboxylate (D140)

(D140)
To a stirred solution of ethyl 4-{[2-amino-5- (trifluoromethyl) phenyl] amino} -1-piperidinecarboxylate (D139, 12.7 g, 38 mmol) in acetonitrile (200 ml) was added 1,1 ′. -Carbonyldiimidazole (9.9 g, 61 mmol) was added in small portions over 10 minutes. The reaction mixture was stirred at room temperature for 5 hours and then the solvent was removed under reduced pressure. The residue was diluted with dichloromethane (200 ml) and extracted with 10% aqueous citric acid (2 × 100 ml). The organic phase was dried over MgSO ₄ and evaporated under reduced pressure to give the title compound (13.5 g, 99% yield) as a brown solid, which was used without further purification (R _f : 0.2). (Ethyl acetate)).

（Ｄ１４１）
アルゴン下、クロロホルム（１５０ｍｌ）中、４−［２−オキソ−６−（トリフルオロメチル）−２，３−ジヒドロ−１Ｈ−ベンズイミダゾール−１−イル］−１−ピペリジンカルボン酸エチル（Ｄ１４０、１３．５ｇ、３８ｍｍｏｌ）の攪拌溶液に、ヨードトリメチルシラン（１７ｍｌ、１２０ｍｍｏｌ）を加えた。反応混合物を１５時間還流した後、冷却した。メタノール（３０ｍｌ）を加え、反応混合物を３０分間攪拌した。沈殿を濾取し、クロロホルムで洗浄した（２×２０ｍｌ）。固体を水（１５０ｍｌ）に溶解し、この溶液を固体水酸化ナトリウムでｐＨ１３の塩基性とした。３０分間攪拌した後、ｐＨ８．５となるまで６Ｍ ＨＣｌを加え、得られた沈殿を濾取した。この固体を４０℃で１５時間真空乾燥させ、標題化合物（１１．１ｇ、収率９７％）を無色の固体として得た（Ｒ_ｆ：ベースライン（酢酸エチル／メタノール（１９：１））。
¹H-NMR (300 MHz, DMSO-d₆): δ7.60 (1H, s), 7.34 (1H, d), 7.14 (1H, d), 4.55 (1H, m), 3.40 (2H, d), 3.05 (2H, t), 2.50 (2H, m), 1.88 (2H, m); m.p. >200℃ (分解) Description 141.1- (4-Piperidinyl) -6- (trifluoromethyl) -1,3-dihydro-2H-benzimidazol-2-one (D141)

(D141)
Ethyl 4- [2-oxo-6- (trifluoromethyl) -2,3-dihydro-1H-benzimidazol-1-yl] -1-piperidinecarboxylate (D140, 13) in chloroform (150 ml) under argon To a stirred solution of .5 g, 38 mmol) was added iodotrimethylsilane (17 ml, 120 mmol). The reaction mixture was refluxed for 15 hours and then cooled. Methanol (30 ml) was added and the reaction mixture was stirred for 30 minutes. The precipitate was collected by filtration and washed with chloroform (2 × 20 ml). The solid was dissolved in water (150 ml) and the solution was basified to pH 13 with solid sodium hydroxide. After stirring for 30 minutes, 6M HCl was added until pH 8.5 and the resulting precipitate was collected by filtration. The solid was dried in vacuo at 40 ° C. for 15 hours to give the title compound (11.1 g, 97% yield) as a colorless solid (R _f : baseline (ethyl acetate / methanol (19: 1)).
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ7.60 (1H, s), 7.34 (1H, d), 7.14 (1H, d), 4.55 (1H, m), 3.40 (2H, d) , 3.05 (2H, t), 2.50 (2H, m), 1.88 (2H, m); mp> 200 ° C (decomposition)

（Ｄ１４２）
室温にてアルゴン下、ジメチルホルムアミド（４０ｍｌ）中、３−フルオロ−４−ニトロトルエン（１０ｇ、０．０６４ｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（１４ｍｌ、０．０８０ｍｏｌ）、次いで４−アミノ−１−ピペリジンカルボン酸１，１−ジメチルエチル（１１．３ｇ、０．０６４ｍｏｌ）で処理した後、９０℃で１８時間加熱した。この混合物を真空濃縮し、残渣を１０％Ｎａ_２ＣＯ_３溶液（１００ｍｌ）で処理し、ジクロロメタンで抽出した（２×１５０ｍｌ）。合わせた抽出液を水（１５０ｍｌ）で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残渣をＥｔ_２Ｏ（２００ｍｌ）で処理し、一晩放置した。生じた結晶を濾別し、Ｅｔ_２Ｏで洗浄し、乾燥させ、標題化合物を橙色固体として得た（１６ｇ、７４％）。
¹H NMRδ(CDCl_3, 400MHz): 1.45-1.65 (2H, m), 1.48 (9H, s), 2.00-2.10 (2H, m), 2.35 (3H, s), 3.00-3.15 (2H, m), 3.62-3.72 (1H, m), 3.92-4.12 (2H, br m), 6.46 (1H, dd), 6.63 (1H, s), 8.07 (1H, d), 8.15 (1H, d) Description 142.4-[(5-Methyl-2-nitrophenyl) amino] -1-piperidinecarboxylic acid 1,1-dimethylethyl (D142)

(D142)
A stirred solution of 3-fluoro-4-nitrotoluene (10 g, 0.064 mol) in dimethylformamide (40 ml) under argon at room temperature was diluted with diisopropylethylamine (14 ml, 0.080 mol) and then 4-amino-1-piperidinecarboxylic acid. After treatment with the acid 1,1-dimethylethyl (11.3 g, 0.064 mol), it was heated at 90 ° C. for 18 hours. The mixture was concentrated in vacuo and the residue was treated with 10% Na ₂ CO ₃ solution (100 ml) and extracted with dichloromethane (2 × 150 ml). The combined extracts were washed with water (150 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was treated with Et ₂ O (200 ml) and left overnight. The resulting crystals were filtered off, washed with Et ₂ O and dried to give the title compound as an orange solid (16 g, 74%).
¹ H NMRδ (CDCl _3, 400MHz): 1.45-1.65 (2H, m), 1.48 (9H, s), 2.00-2.10 (2H, m), 2.35 (3H, s), 3.00-3.15 (2H, m) , 3.62-3.72 (1H, m), 3.92-4.12 (2H, br m), 6.46 (1H, dd), 6.63 (1H, s), 8.07 (1H, d), 8.15 (1H, d)

（Ｄ１４３）
エタノール（３５０ｍｌ）中、４−［（５−メチル−２−ニトロフェニル）アミノ］−１−ピペリジンカルボン酸１，１−ジメチルエチル（Ｄ１４２、１６ｇ、０．０５０ｍｏｌ）の攪拌懸濁液を１０％Ｐｄ／Ｃ（１．５ｇ）で処理し、水素雰囲気下、室温および加圧下で１６時間維持した。この混合物をＫｉｅｓｅｌｇｕｈｒで濾過して触媒を除去し、濾液を真空濃縮し、標題化合物を淡紫色固体として得た（１３．５ｇ、９３％）。
¹H NMRδ(CDCl_3, 400MHz): 1.28-1.52 (2H, m), 1.48 (9H, s), 2.04 (2H, br d), 2.26 (3H, s), 2.90-3.02 (2H, m), 3.20 (3H, br s), 3.35-3.46 (1H, m), 4.02 (2H, br s), 6.46-6.50 (2H, m), 6.64 (1H, d) Description 143.4 4-[(2-Amino-5-methylphenyl) amino] -1-piperidinecarboxylic acid 1,1-dimethylethyl (D143)

(D143)
10% of a stirred suspension of 1,1-dimethylethyl 4-[(5-methyl-2-nitrophenyl) amino] -1-piperidinecarboxylate (D142, 16 g, 0.050 mol) in ethanol (350 ml) Treated with Pd / C (1.5 g) and maintained at room temperature and under pressure for 16 hours under hydrogen atmosphere. The mixture was filtered through Kieselguhr to remove the catalyst and the filtrate was concentrated in vacuo to give the title compound as a pale purple solid (13.5 g, 93%).
¹ H NMRδ (CDCl _3, 400MHz): 1.28-1.52 (2H, m), 1.48 (9H, s), 2.04 (2H, br d), 2.26 (3H, s), 2.90-3.02 (2H, m), 3.20 (3H, br s), 3.35-3.46 (1H, m), 4.02 (2H, br s), 6.46-6.50 (2H, m), 6.64 (1H, d)

（Ｄ１４４）
室温にてアルゴン下、アセトニトリル（３００ｍｌ）中、４−［（２−アミノ−５−メチルフェニル）アミノ］−１−ピペリジンカルボン酸１，１−ジメチルエチル（１３．５ｇ、０．０４４ｍｏｌ）の攪拌溶液を、アセトニトリル（１５０ｍｌ）中、１，１’−カルボニルジイミダゾール（１１．４ｇ、０．０７０ｍｏｌ）の溶液で１０分かけて処理した後、４０℃で６時間、次いで室温で１８時間加熱した。生じた固体を濾別し、アセトニトリルで洗浄し、乾燥させ、４．６ｇの標題化合物を淡紫色固体として得た。濾液を真空濃縮し、残渣をジクロロメタン（３００ｍｌ）に溶解し、水（３×２００ｍｌ）で洗浄した後、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、褐色油状物を得た。これを１：１ＥｔＯＡｃ／６０〜８０石油（２００ｍｌ）で処理し、さらなる標題化合物（５．６ｇ）を結晶化させた。
¹H NMRδ(CDCl_3, 400MHz): 1.52 (9H, s), 1.83 (2H, br d), 2.26-2.45 (2H, m), 2.39 (3H, s), 2.80-3.00 (2H, br m), 4.30 (2H, br s), 4.41-4.52 (1H, m), 6.87 (1H, d), 6.94 (1H, s), 6.98 (1H, d), 9.30 (1H, s) Description 144.4- (6-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1-piperidinecarboxylic acid 1,1-dimethylethyl (D144)

(D144)
Stirring of 1,1-dimethylethyl 4-[(2-amino-5-methylphenyl) amino] -1-piperidinecarboxylate (13.5 g, 0.044 mol) in acetonitrile (300 ml) under argon at room temperature The solution was treated with a solution of 1,1′-carbonyldiimidazole (11.4 g, 0.070 mol) in acetonitrile (150 ml) over 10 minutes, then heated at 40 ° C. for 6 hours and then at room temperature for 18 hours. . The resulting solid was filtered off, washed with acetonitrile and dried to give 4.6 g of the title compound as a pale purple solid. The filtrate was concentrated in vacuo and the residue was dissolved in dichloromethane (300 ml), washed with water (3 × 200 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a brown oil. This was treated with 1: 1 EtOAc / 60-80 petroleum (200 ml) to crystallize additional title compound (5.6 g).
¹ H NMRδ (CDCl _3, 400MHz): 1.52 (9H, s), 1.83 (2H, br d), 2.26-2.45 (2H, m), 2.39 (3H, s), 2.80-3.00 (2H, br m) , 4.30 (2H, br s), 4.41-4.52 (1H, m), 6.87 (1H, d), 6.94 (1H, s), 6.98 (1H, d), 9.30 (1H, s)

（Ｄ１４５）
室温にてアルゴン下、ジクロロメタン（８０ｍｌ）とＭｅＯＨ（２０ｍｌ）の混合物中、４−（６−メチル−２−オキソ−２，３−ジヒドロ−１Ｈ−ベンズイミダゾール−１−イル）−１−ピペリジンカルボン酸１，１−ジメチルエチル（Ｄ１４４、１０．２ｇ、０．０３１ｍｏｌ）の攪拌溶液を、ジオキサン中４ＭのＨＣｌ（３５ｍｌ、０．１４ｍｏｌ）で処理し、室温で２０時間攪拌した。生じた固体を濾別し、Ｅｔ_２Ｏで洗浄し、乾燥させ、標題化合物のＨＣｌ塩を淡灰色固体として得た（７．９５ｇ、９６％）。この材料の大部分（７．８０ｇ）をＤＣＭ（２２０ｍｌ）および１０％Ｎａ_２ＣＯ_３溶液（２００ｍｌ）で処理し、固体が溶解するまでよく振盪した後、ＤＣＭ層を分離し、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、標題化合物をベージュ色の固体として得た（６．８０ｇ）。
¹H NMR (遊離塩基) δ(CDCl₃, 400MHz): 1.64 (1H, br s), 1.80-1.90 (2H, m), 2.30 -2.45 (2H, m), 2.39 (3H, s), 2.75-2.86 (2H, m), 3.23-3.31 (2H, m), 4.38-4.50 (1H, m), 6.86 (1H, d), 6.98 (1H, d), 7.11 (1H, s), 9.50 (1H, br s) Description 145.6-Methyl-1- (4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one (D145)

(D145)
4- (6-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1-piperidinecarboxylic acid in a mixture of dichloromethane (80 ml) and MeOH (20 ml) under argon at room temperature. A stirred solution of the acid 1,1-dimethylethyl (D144, 10.2 g, 0.031 mol) was treated with 4M HCl in dioxane (35 ml, 0.14 mol) and stirred at room temperature for 20 hours. The resulting solid was filtered off, washed with Et ₂ O and dried to give the HCl salt of the title compound as a light gray solid (7.95 g, 96%). Most of this material (7.80 g) was treated with DCM (220 ml) and 10% Na ₂ CO ₃ solution (200 ml) and shaken well until the solid dissolved, then the DCM layer was separated and dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as a beige solid (6.80 g).
¹ H NMR (free base) δ (CDCl ₃ , 400MHz): 1.64 (1H, br s), 1.80-1.90 (2H, m), 2.30 -2.45 (2H, m), 2.39 (3H, s), 2.75- 2.86 (2H, m), 3.23-3.31 (2H, m), 4.38-4.50 (1H, m), 6.86 (1H, d), 6.98 (1H, d), 7.11 (1H, s), 9.50 (1H, br s)

（Ｄ１４６）
アルゴン下、Ｎ，Ｎ−ジメチルホルムアミド（５ｍｌ）中、２，４−ジフルオロ−１−ニトロベンゼン（０．１１５ｍｌ、１．０６ｍｍｏｌ）および１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ５８、３００ｍｇ、０．９６２ｍｍｏｌ）の溶液をジイソプロピルエチルアミン（０．４９ｍｌ、２．８８ｍｍｏｌ）で処理し、反応混合物をマイクロ波反応装置にて１１０℃で４０分間加熱した。次に、得られた混合物を真空濃縮し、残渣を希ＮａＨＣＯ_３溶液（３０ｍｌ）で処理した後、酢酸エチルで抽出した（２×５０ｍｌ）。合わせた抽出液を乾燥させ（ＭｇＳＯ_４）、真空濃縮し、粗材料を橙色残渣として得た。この残渣を０〜１０％メタノール／ジクロロメタンで溶出するシリカゲルでのクロマトグラフィーに付し、標題化合物（１３０ｍｇ、２７％）を黄色残渣として得た。ＭＨ^＋＝３８０ Description 146.1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -N- (5-fluoro-2-nitrophenyl) -4-piperidinamine (D146)

(D146)
2,4-Difluoro-1-nitrobenzene (0.115 ml, 1.06 mmol) and 1- [trans-4- (ethyloxy) -1-methylcyclohexyl]-in N, N-dimethylformamide (5 ml) under argon A solution of 4-piperidineamine dihydrochloride (D58, 300 mg, 0.962 mmol) was treated with diisopropylethylamine (0.49 ml, 2.88 mmol) and the reaction mixture was heated in a microwave reactor at 110 ° C. for 40 minutes. . The resulting mixture was then concentrated in vacuo and the residue was treated with dilute NaHCO ₃ solution (30 ml) and extracted with ethyl acetate (2 × 50 ml). The combined extracts were dried (MgSO ₄ ) and concentrated in vacuo to give the crude material as an orange residue. The residue was chromatographed on silica gel eluting with 0-10% methanol / dichloromethane to give the title compound (130 mg, 27%) as a yellow residue. MH ⁺ = 380

（Ｄ１４７）
室温にてアルゴン下、ＥｔＯＨ（１０ｍｌ）中、１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−Ｎ−（５−フルオロ−２−ニトロフェニル）−４−ピペリジンアミン（Ｄ１４６、１３０ｍｇ、０．３４２ｍｍｏｌ）の攪拌溶液をラネーニッケル（２５ｍｇ）、次いでヒドラジン水和物（１６６μＬ、３．４２ｍｍｏｌ）で処理した。ここの反応混合物を２時間攪拌したところ、最初の黄色が消失していた。Ｋｉｅｓｅｌｇｕｈｒで濾過することで触媒を除去し、濾液を真空濃縮し、標題化合物を灰白色残渣として得た（９７ｍｇ、８１％）。ＭＨ^＋＝３５０ Description 147. (2-Amino-5-fluorophenyl) {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} amine

(D147)
1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -N- (5-fluoro-2-nitrophenyl) -4-piperidineamine (D146, 130 mg) in EtOH (10 ml) under argon at room temperature. , 0.342 mmol) was treated with Raney nickel (25 mg) followed by hydrazine hydrate (166 μL, 3.42 mmol). When the reaction mixture was stirred for 2 hours, the first yellow color disappeared. The catalyst was removed by filtration through Kieselguhr and the filtrate was concentrated in vacuo to give the title compound as an off-white residue (97 mg, 81%). MH ⁺ = 350

（Ｄ１４８）
０℃にてアルゴン下、テトラヒドロフラン（２００ｍｌ）中、ジイイソプロピルアミン（１６．１ｍｌ、１１５ｍｍｏｌ、２．１当量）の攪拌溶液を、ヘキサン中２．５Ｍのｎ−ブチルリチウム（１．０５当量、１１０ｍｍｏｌ、４４ｍｌ）で処理した後、これを同じ温度で１０分間攪拌した。次に、この混合物を、５０ｍｌの乾燥テトラヒドロフラン中、４−（メチルオキシ）シクロヘキサンカルボン酸（１当量、５５ｍｍｏｌ、８．７ｇ）の溶液で処理した。得られた黄色溶液を５０℃で２時間加熱した後、０℃まで冷却し、ヨードメタン（３当量、１２ｍｌ）で処理した。この混合物を室温まで温め、２時間攪拌した。この混合物をクエン酸（１０％水溶液）とＥｔ_２Ｏとで分液し、２層に分け、水層をＥｔ_２Ｏで抽出した（２回）。有機液を合わせ、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、真空濃縮し、シス：トランス異性体の混合物である黄色固体を得た（９．８ｇ）。
¹H NMRδ(d⁶DMSO, 400MHz): 1.078-2.018 (11 H, シス／トランス異性体), 3.074 (1H, m 単一の異性体), 3.193 (3H, s 単一の異性体), 3.213 (3H, s 単一の異性体), 3.606 (1H, s ブロード, 単一の異性体), >12.5 (1H, s ブロード, シス／トランス異性体) Description 148. Cis / trans-1-methyl-4- (methyloxy) cyclohexanecarboxylic acid (D148)

(D148)
A stirred solution of diisopropylamine (16.1 ml, 115 mmol, 2.1 eq) in tetrahydrofuran (200 ml) under argon at 0 ° C. was added 2.5M n-butyllithium in hexane (1.05 eq, 110 mmol). This was stirred at the same temperature for 10 minutes. The mixture was then treated with a solution of 4- (methyloxy) cyclohexanecarboxylic acid (1 eq, 55 mmol, 8.7 g) in 50 ml of dry tetrahydrofuran. The resulting yellow solution was heated at 50 ° C. for 2 hours, then cooled to 0 ° C. and treated with iodomethane (3 eq, 12 ml). The mixture was warmed to room temperature and stirred for 2 hours. The mixture was partitioned between citric acid (10% aqueous solution) and Et ₂ O, separated into two layers, and the aqueous layer was extracted with Et ₂ O (twice). The organics were combined, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a yellow solid (9.8 g) that was a mixture of cis: trans isomers.
¹ H NMRδ (d ⁶ DMSO, 400 MHz): 1.078-2.018 (11 H, cis / trans isomer), 3.074 (1H, m single isomer), 3.193 (3H, s single isomer), 3.213 (3H, s single isomer), 3.606 (1H, s broad, single isomer),> 12.5 (1H, s broad, cis / trans isomer)

（Ｄ１４９）
シス／トランス−１−メチル−４−（メチルオキシ）シクロヘキサンカルボン酸（Ｄ１４８、４１．３ｍｍｏｌ、７．７ｇ）を塩化チオニル（１５．３当量、６３１ｍｍｏｌ、４６ｍｌ）に溶解した。この混合物を９０℃で４時間還流した。溶媒を蒸発させ、粗生成物をトルエンで処理し、真空濃縮した。残った褐色油状物を５％Ｎａ_２ＣＯ_３溶液（４００ｍｌ）およびテトラヒドロフラン（４０ｍｌ）で処理し、この混合物を室温で３０分間攪拌した。この水溶液をＥｔ_２Ｏで洗浄し（２回）、水相を２Ｍ ＨＣｌで酸性化し、酢酸エチルで抽出した（２回）。合わせた有機液をＮａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させ、標題化合物を得た（２．８ｇ、４０％）。
¹H NMR δ(d⁶DMSO, 400MHz): 1.085 (3H, s), 1.419 (2H, m), 1.485 (4H, m), 1.701 (2H, m), 3.225 (4H, m), 3.342 (1H, s) Description 149. Trans-1-methyl-4- (methyloxy) cyclohexanecarboxylic acid (D149)

(D149)
Cis / trans-1-methyl-4- (methyloxy) cyclohexanecarboxylic acid (D148, 41.3 mmol, 7.7 g) was dissolved in thionyl chloride (15.3 eq, 631 mmol, 46 ml). The mixture was refluxed at 90 ° C. for 4 hours. The solvent was evaporated and the crude product was treated with toluene and concentrated in vacuo. The remaining brown oil was treated with 5% Na ₂ CO ₃ solution (400 ml) and tetrahydrofuran (40 ml) and the mixture was stirred at room temperature for 30 minutes. The aqueous solution was washed with Et ₂ O (2 times) and the aqueous phase was acidified with 2M HCl and extracted with ethyl acetate (2 times). The combined organics were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated to give the title compound (2.8 g, 40%).
¹ H NMR δ (d ⁶ DMSO, 400MHz): 1.085 (3H, s), 1.419 (2H, m), 1.485 (4H, m), 1.701 (2H, m), 3.225 (4H, m), 3.342 (1H , s)

（Ｄ１５０）
室温にて、乾燥トルエン（７０ｍｌ）中、トランス−１−メチル−４−（メチルオキシ）シクロヘキサンカルボン酸（Ｄ１４９、１５．０ｍｍｏｌ、２．８ｇ）の溶液に、Ｅｔ_３Ｎ（１．３当量、１９．６ｍｍｏｌ、２．７ｍｌ）およびアジ化ジフェニルホスホリル（１．０当量、１５．０ｍｍｏｌ、３．２ｍｌ）を加えた。この混合物を８０℃で２時間還流した。この混合物を室温まで冷却し、１Ｍ ＮａＯＨ（７０ｍｌ）に注ぎ、この水溶液をＥｔＯＡで抽出した（２回）。有機液を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させ、粗化合物を得た。次に、粗生成物をシリカカラムでのクロマトグラフィー（ＥｔＯＡｃ−ｎｈｅｘ）により精製し、標題化合物を得た（１．３３ｇ、４８％）。
¹H NMR δ(d⁶DMSO, 400MHz): 1.327 (3H, s), 1.61 (8H, m), 3.197 (3H, s) 3.355 (1H, m) Description 150. Trans-1-isocyanato-1-methyl-4- (methyloxy) cyclohexane (D150)

(D150)
To a solution of trans-1-methyl-4- (methyloxy) cyclohexanecarboxylic acid (D149, 15.0 mmol, 2.8 g) in dry toluene (70 ml) at room temperature was added Et ₃ N (1.3 eq., 19.6 mmol, 2.7 ml) and diphenylphosphoryl azide (1.0 eq, 15.0 mmol, 3.2 ml) were added. The mixture was refluxed at 80 ° C. for 2 hours. The mixture was cooled to room temperature, poured into 1M NaOH (70 ml) and the aqueous solution was extracted with EtOA (twice). The organics were combined, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated to give the crude compound. The crude product was then purified by chromatography on a silica column (EtOAc-nhex) to give the title compound (1.33 g, 48%).
¹ H NMR δ (d ⁶ DMSO, 400MHz): 1.327 (3H, s), 1.61 (8H, m), 3.197 (3H, s) 3.355 (1H, m)

（Ｄ１５１）
室温にて、ＴＨＦ（３０ｍｌ）中、トランス−１−イソシアナト−１−メチル−４−（メチルオキシ）シクロヘキサン（Ｄ１５０、７．２７ｍｍｏｌ、１．３３ｇ）の溶液に濃ＨＣｌ（６ｍｌ）を加えた。この混合物を４時間室温で攪拌し、濃ＨＣｌ（数滴）を加えた。一晩放置して反応させ、溶媒を蒸発させ、標題化合物を得た（０．９ｇ、６９％）。
¹H NMR δ(d⁶DMSO, 400MHz): 1.260 (3H, s), 1.39 (2H, m), 1.632 (4H, m), 1.87 (2H, m), 3.157 (1H, m), 3.217 (3H, s) Description 151. Trans-1-methyl-4- (methyloxy) cyclohexaneamine monohydrochloride (D151)

(D151)
Concentrated HCl (6 ml) was added to a solution of trans-1-isocyanato-1-methyl-4- (methyloxy) cyclohexane (D150, 7.27 mmol, 1.33 g) in THF (30 ml) at room temperature. The mixture was stirred for 4 hours at room temperature and concentrated HCl (a few drops) was added. The reaction was allowed to stand overnight and the solvent was evaporated to give the title compound (0.9 g, 69%).
¹ H NMR δ (d ⁶ DMSO, 400MHz): 1.260 (3H, s), 1.39 (2H, m), 1.632 (4H, m), 1.87 (2H, m), 3.157 (1H, m), 3.217 (3H , s)

（Ｄ１５２）
トランス−１−メチル−４−（メチルオキシ）シクロヘキサンアミン一塩酸塩（Ｄ１５１、７．６９ｍｍｏｌ、１．１ｇ）、１−エチル−１−メチル−４−オキソピペリジニウムヨージド（Ｄ４９、１．７当量、１３．１ｍｍｏｌ）、３．５ｇ、Ｋ_２ＣＯ_３（１．５当量、１１．５ｍｍｏｌ、１．５ｇ）、水（４０ｍｌ）およびエタノール（８０ｍｌ）を、ＴＬＣで出発材料が見られなくなるまで８０℃で還流した。この混合物をＮａＨＣＯ_３とジクロロメタンとで分液した。いくらかの生成物が機械の漏れのために失われた。後処理を繰り返した。次に、粗生成物をシリカカラムでのクロマトグラフィー（ＭｅＯＨ−ＮＨ_３−ジクロロメタン）により精製し、標題化合物を得た（６５０ｍｇ、３５％）。
¹H NMR δ(d⁶DMSO, 400MHz) 0.85 (3H, s), 1.50 (8H, m)1.762 (2H, t), 2.301 (4H, t), 2.725 (4H, t), 3.207 (3H, s), 3.274 (1H, m) Description 152.1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinone (D152)

(D152)
Trans-1-methyl-4- (methyloxy) cyclohexaneamine monohydrochloride (D151, 7.69 mmol, 1.1 g), 1-ethyl-1-methyl-4-oxopiperidinium iodide (D49, 1. 7 equivalents, 13.1 mmol), 3.5 g, K ₂ CO ₃ (1.5 equivalents, 11.5 mmol, 1.5 g), water (40 ml) and ethanol (80 ml), no starting material seen in TLC Until reflux at 80 ° C. The mixture was partitioned between NaHCO ₃ and dichloromethane. Some product was lost due to machine leaks. The post-treatment was repeated. The crude product was chromatographed on a silica column (MeOH-NH ₃ - dichloromethane) to give the title compound (650 mg, 35%).
¹ H NMR δ (d ⁶ DMSO, 400MHz) 0.85 (3H, s), 1.50 (8H, m) 1.762 (2H, t), 2.301 (4H, t), 2.725 (4H, t), 3.207 (3H, s ), 3.274 (1H, m)

（Ｄ１５３）
メタノール中２ＭのＮＨ_３（１５．０当量、４０．０ｍｍｏｌ、２０ｍｌ）中、１−［トランス−１−メチル−４−（メチルオキシ）シクロヘキシル］−４−ピペリジノン（Ｄ１５２、２．６７ｍｍｏｌ、６５０ｍｇ）の溶液に、１０％Ｐｄ／Ｃペースト（６５ｍｇ）を加えた。この混合物を室温にて２４時間、５０ｐｓｉで水素化した。この混合物をｋｉｅｓｅｌｇｕｈｒで濾過し、エタノール（１００ｍｌ）で洗浄した。溶媒を蒸発させ、粗生成物を得た。この粗生成物に対して反応を繰り返し、２４時間放置した。この混合物をセライトで濾過し、エタノールで洗浄し、溶媒を蒸発させ、標題化合物を得た（３９０ｍｇ、６８％、Ｍ^＋＋Ｈ＝２２７）。 Description 153.1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidineamine (D153)

(D153)
1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinone (D152, 2.67 mmol, 650 mg) in 2M NH _{3 in} methanol (15.0 eq, 40.0 mmol, 20 ml). To the solution was added 10% Pd / C paste (65 mg). The mixture was hydrogenated at 50 psi for 24 hours at room temperature. The mixture was filtered through kieselguhr and washed with ethanol (100 ml). The solvent was evaporated to give the crude product. The reaction was repeated on this crude product and left for 24 hours. The mixture was filtered through celite, washed with ethanol and the solvent was evaporated to give the title compound (390 mg, 68%, M ⁺ + H = 227).

（Ｄ１５４）
アルゴン下、Ｎ，Ｎ−ジメチルホルムアミド（５ｍｌ）中、１−［トランス−４−（メチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ１５３、３０６ｍｇ、１．０２ｍｍｏｌ）の溶液に、ジイソプロピルエチルアミン（０．５５ｍＬ、３．２３ｍｍｏｌ）および２，４−ジフルオロ−１−ニトロベンゼン（１２３μＬ、１．１２ｍｍｏｌ）を加えた。この反応物をマイクロ波反応装置にて１００℃で３０分間、次いでさらに３０分間加熱した。この混合物を飽和ＮａＨＣＯ_３（５０ｍＬ）に注ぎ、ＥｔＯＡｃで抽出した（３回）。合わせた有機液をブライン、Ｈ_２Ｏおよびブラインで順次洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、回転蒸発により濃縮した。粗残渣をＳＣＸ（５ｇ）により精製した後、クロマトグラフィーに付し（シリカ、ＣＨ_２Ｃｌ_２〜０．５％ＮＨ_３／９．５％ＭｅＯＨ／９０％ＣＨ_２Ｃｌ_２）、黄色油状物を得た。次に、黄色油状物をクロマトグラフィーに付し（アミンドープシリカ、ヘキサン−ＥｔＯＡｃ）、標題化合物（２０４ｍｇ、５５％）を黄色油状物として得た。ＭＨ^＋３６６ Description 154. N- (5-fluoro-2-nitrophenyl) -1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidineamine (D154)

(D154)
Solution of 1- [trans-4- (methyloxy) -1-methylcyclohexyl] -4-piperidineamine dihydrochloride (D153, 306 mg, 1.02 mmol) in N, N-dimethylformamide (5 ml) under argon To was added diisopropylethylamine (0.55 mL, 3.23 mmol) and 2,4-difluoro-1-nitrobenzene (123 μL, 1.12 mmol). The reaction was heated in a microwave reactor at 100 ° C. for 30 minutes and then for an additional 30 minutes. The mixture was poured into saturated NaHCO ₃ (50 mL) and extracted with EtOAc (3 times). The combined organics were washed sequentially with brine, H ₂ O and brine, dried (Na ₂ SO ₄ ) and concentrated by rotary evaporation. The crude residue was purified by SCX (5 g) and then chromatographed (silica, CH ₂ Cl _{2 to} 0.5% NH ₃ /9.5% MeOH / 90% CH ₂ Cl ₂ ) to give a yellow oil. Obtained. The yellow oil was then chromatographed (amine-doped silica, hexane-EtOAc) to give the title compound (204 mg, 55%) as a yellow oil. MH ⁺ 366

（Ｄ１５５）
アルゴン下、ＥｔＯＨ（１０ｍＬ）中、Ｎ−（５−フルオロ−２−ニトロフェニル）−１−［トランス−１−メチル−４−（メチルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ１５４、２４５ｍｇ、０．６７ｍｍｏｌ）の激しく攪拌した溶液に、ラネーニッケル（０．２５ｍＬ、Ｈ_２Ｏ中１０％溶液）を加えた。ヒドラジン水和物（２２０μＬ、７．０６ｍｍｏｌ）を滴下し、次いでさらなるラネーニッケル（０．２５ｍＬ、Ｈ_２Ｏ中１０％溶液）を追加した。この反応物を１時間攪拌した後、ＥｔＯＨを用い、Ｋｉｅｓｅｌｇｕｈｒで濾過した。回転蒸発により溶媒を除去し、標題化合物（２０５ｍｇ、９１％）を褐色油状物として得、これは放置すると固化して褐色固体となった。ＭＨ^＋３３６ Description 155. (2-Amino-5-fluorophenyl) {1- [trans-4- (methyloxy) -1-methylcyclohexyl] -4-piperidinyl} amine (D155)

(D155)
N- (5-Fluoro-2-nitrophenyl) -1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidineamine (D154, 245 mg, 0 in EtOH (10 mL) under argon. Raney nickel (0.25 mL, 10% solution in H ₂ O) was added to a vigorously stirred solution of .67 mmol). Hydrazine hydrate (220 μL, 7.06 mmol) was added dropwise, followed by additional Raney nickel (0.25 mL, 10% solution in H ₂ O). The reaction was stirred for 1 hour and then filtered through Kieselguhr using EtOH. The solvent was removed by rotary evaporation to give the title compound (205 mg, 91%) as a brown oil that solidified on standing to a brown solid. MH ⁺ 336

（Ｄ１５６）
室温にてアルゴン下、Ｎ，Ｎ−ジメチルホルムアミド（５ｍｌ）中、１−［トランス−４−（メチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ１５３、３１８ｍｇ、１．０６ｍｍｏｌ）の溶液に、ジイソプロピルエチルアミン（０．５３ｍＬ、３．１２ｍｍｏｌ）および６−クロロ−２−フルオロ−１−ニトロベンゼン（１９７ｍｇ、１．１２ｍｍｏｌ）を加えた。この反応物をマイクロ波反応装置にて１１０℃で３０分間加熱した後、さらに３０分後にさらなる６−クロロ−２−フルオロ−１−ニトロベンゼン（８１ｍｇ、０．４６ｍｍｏｌ）を追加した。この反応物を飽和ＮａＨＣＯ_３（５０ｍＬ）に注ぎ、ＥｔＯＡｃで抽出した（３回）。合わせた有機液をブライン、Ｈ_２Ｏおよびブラインで順次洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、回転蒸発により濃縮した。粗残渣をＳＣＸ（５ｇ）により精製した後、クロマトグラフィーに付し（シリカ、ＣＨ_２Ｃｌ_２〜０．５％ＮＨ_３／９．５％ＭｅＯＨ／９０％ＣＨ_２Ｃｌ_２）、標題化合物（３２３ｍｇ、８５％）を黄色油状物として得た。
M(Cl-35)⁺ 382, M(Cl-37)H⁺ 384 Description D156. N- (5-chloro-2-nitrophenyl) -1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidineamine (D156)

(D156)
1- [trans-4- (methyloxy) -1-methylcyclohexyl] -4-piperidineamine dihydrochloride (D153, 318 mg, 1.06 mmol) in N, N-dimethylformamide (5 ml) under argon at room temperature. ) Was added diisopropylethylamine (0.53 mL, 3.12 mmol) and 6-chloro-2-fluoro-1-nitrobenzene (197 mg, 1.12 mmol). The reaction was heated in a microwave reactor at 110 ° C. for 30 minutes, then additional 30 minutes later additional 6-chloro-2-fluoro-1-nitrobenzene (81 mg, 0.46 mmol) was added. The reaction was poured into saturated NaHCO ₃ (50 mL) and extracted with EtOAc (3 ×). The combined organics were washed sequentially with brine, H ₂ O and brine, dried (Na ₂ SO ₄ ) and concentrated by rotary evaporation. The crude residue was purified by SCX (5 g) and then chromatographed (silica, CH ₂ Cl _{2 to} 0.5% NH ₃ /9.5% MeOH / 90% CH ₂ Cl ₂ ) to give the title compound (323 mg 85%) as a yellow oil.
M (Cl-35) ⁺ 382, M (Cl-37) H ⁺ 384

（Ｄ１５７）
室温にてアルゴン下、Ｎ−（５−クロロ−２−ニトロフェニル）−１−［トランス−１−メチル−４−（メチルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ１５６、３２３ｍｇ、０．８５ｍｍｏｌ）をＥｔＯＨ（１０ｍＬ）中で激しく攪拌した。ラネーニッケル（０．２５ｍＬ、Ｈ_２Ｏ中１０％溶液）、次いでヒドラジン水和物（２６０μＬ、８．３５ｍｍｏｌ）を加えた。さらなるラネーニッケル（０．２５ｍＬ、Ｈ_２Ｏ中１０％溶液）を追加し、この反応物を３０分間激しく攪拌した。この混合物を、ＥｔＯＨを用いてＫｉｅｓｅｌｇｕｈｒで濾過し、回転蒸発により濃縮し、標題化合物（３０５ｍｇ）を金〜褐色固体として得た。
M(Cl-35)⁺ 352, M(Cl-37)H⁺ 354 Description D157. (2-Amino-5-chlorophenyl) {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} amine (D157)

(D157)
N- (5-chloro-2-nitrophenyl) -1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidineamine (D156, 323 mg, 0.85 mmol) under argon at room temperature Was vigorously stirred in EtOH (10 mL). Raney nickel (0.25 mL, 10% solution in H ₂ O) was added followed by hydrazine hydrate (260 μL, 8.35 mmol). Additional Raney nickel (0.25 mL, 10% solution in H ₂ O) was added and the reaction was stirred vigorously for 30 minutes. The mixture was filtered through Kieselguhr with EtOH and concentrated by rotary evaporation to give the title compound (305 mg) as a gold-brown solid.
M (Cl-35) ⁺ 352, M (Cl-37) H ⁺ 354

（Ｄ１５８）
ブタン−２−オン（１００ｍｌ）中、３−フルオロ−４−ニトロフェノール（３ｇ）、ヨードエタン（３ｍｌ）および炭酸カリウム（５．５ｇ）の溶液を８５℃で２．５時間加熱した。この混合物を冷却し、濾過し、濾液を蒸発させた。ヘキサンでのトリチュレーションにより、標題化合物を灰白色固体として得た（３ｇ）。 Description 158.2 2-Fluoro-4-ethoxy-1-nitrobenzene (D158)

(D158)
A solution of 3-fluoro-4-nitrophenol (3 g), iodoethane (3 ml) and potassium carbonate (5.5 g) in butan-2-one (100 ml) was heated at 85 ° C. for 2.5 hours. The mixture was cooled, filtered and the filtrate was evaporated. Trituration with hexanes afforded the title compound as an off-white solid (3g).

（Ｄ１５９）
マイクロ波容器に２−フルオロ−４−エトキシ−１−ニトロベンゼン（Ｄ１５８、０．３ｇ）、１−［トランス−１−メチル−４−（メトキシ）シクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ１５３の二塩酸塩、０．３ｇ）、ジメチルホルムアミド（４ｍｌ）およびジイソプロピルエチルアミン（１．０ｍｌ）を入れ、マイクロ波反応装置にて２００℃で２０分間加熱した。冷却反応物を蒸発させ、メタノールに溶解し、ＳＣＸカートリッジに乗せ、メタノール、次いで２Ｍメタノール性アンモニアで溶出した。メタノール性アンモニア画分を蒸発させ、残渣を０〜５％ジクロロメタン−メタノール性アンモニアで溶出するシリカゲルでのクロマトグラフィーに付し、標題化合物を黄色ガラスとして得た（０．３５８ｇ）。ＭＨ^＋＝３９２ Description 159. N- [5- (ethyloxy) -2-nitrophenyl] -1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinamine (D159)

(D159)
In a microwave container was added 2-fluoro-4-ethoxy-1-nitrobenzene (D158, 0.3 g), 1- [trans-1-methyl-4- (methoxy) cyclohexyl] -4-piperidinamine dihydrochloride (D153 Dihydrochloride, 0.3 g), dimethylformamide (4 ml) and diisopropylethylamine (1.0 ml) were added and heated in a microwave reactor at 200 ° C. for 20 minutes. The cooled reaction was evaporated, dissolved in methanol, loaded onto an SCX cartridge and eluted with methanol followed by 2M methanolic ammonia. The methanolic ammonia fraction was evaporated and the residue was chromatographed on silica gel eluting with 0-5% dichloromethane-methanolic ammonia to give the title compound as a yellow glass (0.358 g). MH ⁺ = 392

（Ｄ１６０）
エタノール（５０ｍｌ）中、Ｎ−［５−（エチルオキシ）−２−ニトロフェニル］−１−［トランス−１−メチル−４−（メチルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ１５９、０．３５ｇ）の溶液、ラネーニッケル（〜２ｍｌ）およびヒドラジン水和物（２ｍｌ）を４０℃で３０分間攪拌した後、冷却し、濾過し、濾液を蒸発させ、エタノールと共沸し、標題化合物をガラスとして得た（０．２６ｇ）。ＭＨ^＋＝３６２ Wherein 160.4- ^(ethyloxy) -N 2 - {1- [frans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D160)

(D160)
N- [5- (ethyloxy) -2-nitrophenyl] -1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinamine (D159, 0.35 g) in ethanol (50 ml) , Raney nickel (˜2 ml) and hydrazine hydrate (2 ml) were stirred at 40 ° C. for 30 minutes then cooled, filtered and the filtrate evaporated and azeotroped with ethanol to give the title compound as a glass (0.26 g). MH ⁺ = 362

（Ｄ１６１）
マイクロ波容器に２−フルオロ−４−エトキシ−１−ニトロベンゼン（Ｄ１５８、０．３ｇ）、１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ５８、０．３１２ｇ）、ジメチルホルムアミド（４ｍｌ）およびジイソプロピルエチルアミン（１．０ｍｌ）を入れ、マイクロ波反応装置にて２００℃で２０分間加熱した。冷却反応物を蒸発させ、メタノールに溶解し、ＳＣＸカートリッジに乗せ、メタノール、次いで２Ｍメタノール性アンモニアで溶出した。メタノール性アンモニア画分を蒸発させ、残渣を０〜５％ジクロロメタン−メタノール性アンモニアで溶出するシリカゲルでのクロマトグラフィーに付し、標題化合物を黄色ガラスとして得た（０．１２３ｇ）。ＭＨ^＋＝４０６ Description 161. N- [5- (ethyloxy) -2-nitrophenyl] -1- [trans-1-methyl-4- (ethyloxy) cyclohexyl] -4-piperidinamine (D161)

(D161)
In a microwave container was added 2-fluoro-4-ethoxy-1-nitrobenzene (D158, 0.3 g), 1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidineamine dihydrochloride (D58, 0.312 g), dimethylformamide (4 ml) and diisopropylethylamine (1.0 ml) were added and heated in a microwave reactor at 200 ° C. for 20 minutes. The cooled reaction was evaporated, dissolved in methanol, loaded onto an SCX cartridge and eluted with methanol followed by 2M methanolic ammonia. The methanolic ammonia fraction was evaporated and the residue was chromatographed on silica gel eluting with 0-5% dichloromethane-methanolic ammonia to give the title compound as a yellow glass (0.123 g). MH ⁺ = 406

（Ｄ１６２）
エタノール（３０ｍｌ）中、Ｎ−［５−（エチルオキシ）−２−ニトロフェニル］−１−［トランス−１−メチル−４−（エチルオキシ）シクロヘキシル］−４−ピペリジンアミン（Ｄ１６１、０．１２３ｇ）の溶液、ラネーニッケル（〜１ｍｌ）およびヒドラジン水和物（１ｍｌ）を４０℃で３０分間攪拌した後、冷却し、濾過し、濾液を蒸発させ、エタノールと共沸し、標題化合物をガラスとして得た（０．０９２ｇ）。ＭＨ^＋＝３７６ Wherein 162.4- ^(ethyloxy) -N 2 - {1- [frans-1-methyl-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D162)

(D162)
Of N- [5- (ethyloxy) -2-nitrophenyl] -1- [trans-1-methyl-4- (ethyloxy) cyclohexyl] -4-piperidinamine (D161, 0.123 g) in ethanol (30 ml) The solution, Raney nickel (˜1 ml) and hydrazine hydrate (1 ml) were stirred at 40 ° C. for 30 minutes then cooled and filtered, the filtrate was evaporated and azeotroped with ethanol to give the title compound as a glass ( 0.092 g). MH ⁺ = 376

（Ｄ１６３）
室温にてアルゴン下、Ｎ，Ｎ−ジメチルホルムアミド（５ｍｌ）中、１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジンアミン二塩酸塩（Ｄ５８、３１８ｍｇ、１．０２ｍｍｏｌ）の溶液に、ジイソプロピルエチルアミン（０．５２ｍＬ、３．０６ｍｍｏｌ）および４−クロロ−２−フルオロ−１−ニトロベンゼン（３６４ｍｇ、２．０７ｍｍｏｌ）を加えた。この反応物をマイクロ波反応装置にて１１０℃で３０分間加熱した後、この混合物を飽和ＮａＨＣＯ_３（５０ｍＬ）に注ぎ、ＥｔＯＡｃで抽出した（３回）。合わせた有機液をブライン、Ｈ_２Ｏおよびブラインで順次洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、回転蒸発により濃縮した。粗残渣をＳＣＸ（５ｇ）により精製した後、クロマトグラフィーに付し（シリカ、ＣＨ_２Ｃｌ_２〜０．５％ＮＨ_３／９．５％ＭｅＯＨ／９０％ＣＨ_２Ｃｌ_２）、標題化合物（１５３ｍｇ、３８％）を黄色油状物として得た。M(Cl-35)⁺ 396, M(Cl-37)H⁺ 398 Description 163. N- (5-chloro-2-nitrophenyl) -1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidineamine (D163)

(D163)
1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinamine dihydrochloride (D58, 318 mg, 1.02 mmol) in N, N-dimethylformamide (5 ml) under argon at room temperature To a solution of was added diisopropylethylamine (0.52 mL, 3.06 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (364 mg, 2.07 mmol). After the reaction was heated in a microwave reactor at 110 ° C. for 30 minutes, the mixture was poured into saturated NaHCO ₃ (50 mL) and extracted with EtOAc (3 ×). The combined organics were washed sequentially with brine, H ₂ O and brine, dried (Na ₂ SO ₄ ) and concentrated by rotary evaporation. The crude residue was purified by SCX (5 g) and then chromatographed (silica, CH ₂ Cl _{2 to} 0.5% NH ₃ /9.5% MeOH / 90% CH ₂ Cl ₂ ) to give the title compound (153 mg 38%) as a yellow oil. M (Cl-35) ⁺ 396, M (Cl-37) H ⁺ 398

（Ｄ１６４）
アルゴン下、Ｎ−（５−クロロ−２−ニトロフェニル）−１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジンアミン（Ｄ１６３、１５３ｍｇ、０．４０ｍｍｏｌ）をＥｔＯＨ（１０ｍＬ）中で激しく攪拌した。ラネーニッケル（０．２５ｍＬ、Ｈ_２Ｏ中１０％溶液）、次いでヒドラジン水和物（１３０μＬ、４．１７ｍｍｏｌ）を加えた。さらなるラネーニッケル（０．２５ｍＬ、Ｈ_２Ｏ中１０％溶液）を追加し、この反応物を３０分間激しく攪拌した。この混合物を、ＥｔＯＨを用いてＫｉｅｓｅｌｇｕｈｒで濾過し、回転蒸発により濃縮し、標題化合物（１３９ｍｇ、９５％）を黄色油状物として得た。M(Cl-35)⁺ 366, M(Cl-37)H⁺ 368 Description 164. (2-Amino-5-chlorophenyl) {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} amine (D164)

(D164)
Under argon, N- (5-chloro-2-nitrophenyl) -1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinamine (D163, 153 mg, 0.40 mmol) was added to EtOH (10 mL). ) Vigorously stirred. Raney nickel (0.25 mL, 10% solution in H ₂ O) was added followed by hydrazine hydrate (130 μL, 4.17 mmol). Additional Raney nickel (0.25 mL, 10% solution in H ₂ O) was added and the reaction was stirred vigorously for 30 minutes. The mixture was filtered through Kieselguhr with EtOH and concentrated by rotary evaporation to give the title compound (139 mg, 95%) as a yellow oil. M (Cl-35) ⁺ 366, M (Cl-37) H ⁺ 368

（Ｅ１）
０℃にて、ジクロロメタン（２０ｍｌ）中、シス５−メチル−Ｎ−［１−（４−メトキシシクロヘキシル）−４−ピペリジニル］−１，２−ベンゼンジアミン（Ｄ７、３２０ｍｇ；０．９ｍｍｏｌ）の溶液をトリホスゲン（１１０ｍｇ、０．４当量）、次いでジイソプロピルエチルアミン（０．２３ｍｌ、１．５当量）で処理した後、０℃で１時間維持した。この混合物をｐＨ９において水で洗浄した。乾燥させ、蒸発させ、クロマトグラフィー（２０ｇシリカ、ジクロロメタン中０〜１０％メタノール）により、ジエチルエーテルから２２０ｍｇ（７１％）の遊離塩基化合物を得た。次に、これをジエチルエーテルから２３０ｍｇの塩酸塩へ変換した（２３０ｍｇ）。
¹H NMR (HCl 塩)δ(d⁶DMSO): 1.4 (2H, m), 1.7 (2H, m), 1.8-2.1 (6H, m), 2.35 (3H, s), 2.9 (2H, m), 3.2 (3H, s), 3.2-3.6 (6H, m), 4.55 (1H, m), 6.8 (2H, ABq), 7.5 (1H, s), 10.55 (1H, br s), 10.8 (1H, s), MH+ 344 Example 1.6 -Methyl-1- [1- (cis-4-methoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E1)

(E1)
A solution of cis 5-methyl-N- [1- (4-methoxycyclohexyl) -4-piperidinyl] -1,2-benzenediamine (D7, 320 mg; 0.9 mmol) in dichloromethane (20 ml) at 0 ° C. Was treated with triphosgene (110 mg, 0.4 equiv) followed by diisopropylethylamine (0.23 ml, 1.5 equiv) and then maintained at 0 ° C. for 1 hour. The mixture was washed with water at pH9. Drying, evaporation and chromatography (20 g silica, 0-10% methanol in dichloromethane) gave 220 mg (71%) of the free base compound from diethyl ether. This was then converted from diethyl ether to 230 mg of hydrochloride (230 mg).
¹ H NMR (HCl salt) δ (d ⁶ DMSO): 1.4 (2H, m), 1.7 (2H, m), 1.8-2.1 (6H, m), 2.35 (3H, s), 2.9 (2H, m) , 3.2 (3H, s), 3.2-3.6 (6H, m), 4.55 (1H, m), 6.8 (2H, ABq), 7.5 (1H, s), 10.55 (1H, br s), 10.8 (1H, s), MH + 344

（Ｅ２）
０℃にて、ジクロロメタン（６ｍｌ）中、トランス５−メチル−Ｎ−［１−（４−メトキシシクロヘキシル）−４−ピペリジニル］−１，２−ベンゼンジアミン（Ｄ８、１００ｍｇ、０．３ｍｍｏｌ）の溶液をトリホスゲン（４０ｍｇ、０．４当量）、次いでジイソプロピルエチルアミン（０．０８ｍｌ、１．５当量）で処理した後、０℃で１時間維持した。この混合物をｐＨ９において水で洗浄した。乾燥させ、蒸発させ、クロマトグラフィー（１０ｇシリカ、ジクロロメタン中０〜１０％メタノール）により、ジエチルエーテルから標題化合物を塩酸塩として単離した（６５ｍｇ）。
¹H NMR (塩酸塩) δ(d⁶DMSO): 1.2 (2H, m), 1.6 (2H, m), 1.9 (2H, m), 2.15 (4H, m), 2.35 (3H, s), 2.9 (2H, m), 3.25 (3H, s), 3.1-3.6 (6H, m), 4.55 (1H, m), 6.8 (2H, ABq), 7.5 (1H, s), 10.55 (1H, br s), 10.8 (1H, s), MH+ 344 Example 2. 6-Methyl-1- [1- (trans-4-methoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E2)

(E2)
A solution of trans 5-methyl-N- [1- (4-methoxycyclohexyl) -4-piperidinyl] -1,2-benzenediamine (D8, 100 mg, 0.3 mmol) in dichloromethane (6 ml) at 0 ° C. Was treated with triphosgene (40 mg, 0.4 equiv) followed by diisopropylethylamine (0.08 ml, 1.5 equiv) and then maintained at 0 ° C. for 1 hour. The mixture was washed with water at pH9. The title compound was isolated as the hydrochloride salt from diethyl ether (65 mg) by drying, evaporation and chromatography (10 g silica, 0-10% methanol in dichloromethane).
¹ H NMR (hydrochloride) δ (d ⁶ DMSO): 1.2 (2H, m), 1.6 (2H, m), 1.9 (2H, m), 2.15 (4H, m), 2.35 (3H, s), 2.9 (2H, m), 3.25 (3H, s), 3.1-3.6 (6H, m), 4.55 (1H, m), 6.8 (2H, ABq), 7.5 (1H, s), 10.55 (1H, br s) , 10.8 (1H, s), MH + 344

（Ｅ３）
室温にて、ジクロロメタン（１０ｍｌ）中、（２−アミノ−５−メチルフェニル）｛１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝アミン（Ｄ１４、１１０ｍｇ、０．３３ｍｍｏｌ）の溶液に、ジイソプロピルエチルアミン（０．０８５ｍｌ、１．５当量、０．５０ｍｍｏｌ）を加えた。この混合物を０℃まで冷却し、ビス（トリクロロメチル）カーボネート（４０ｍｇ、０．４当量、０．１３ｍｍｏｌ）を加えた。３０分後、この混合物を水に注ぎ、この水溶液をジクロロメタンで抽出し（２回）、有機液をブラインおよび水で交互に洗浄した（２回）。有機液を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させた。生成物をＨＣｌ（ジエチルエーテル中１Ｍ溶液３ｍｌ）で処理し、標題生成物を得た（４４ｍｇｓ、３７％）。Ｍ^＋−Ｈ＝３５６
¹H NMR (塩酸塩)δ(d⁶DMSO, 400MHz) 1.093 (3H, t), 1.221 (2H, m), 1.542 (2H, m) 1.887 (2H, m) 2.108 (3H, d) 2.333 (3H, s) 2.782 (2H, m), 3.202 (4H, m) 3.473 (4H, m) 4.542 (1H, m) 6.805 (1H, d) 6.871 (1H, d) 7.345 (1H, s), 10.00 (1H, br), 10.80 (1H, s) Example 3.1 1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6-methyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E3)

(E3)
A solution of (2-amino-5-methylphenyl) {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} amine (D14, 110 mg, 0.33 mmol) in dichloromethane (10 ml) at room temperature Was added diisopropylethylamine (0.085 ml, 1.5 eq, 0.50 mmol). The mixture was cooled to 0 ° C. and bis (trichloromethyl) carbonate (40 mg, 0.4 eq, 0.13 mmol) was added. After 30 minutes, the mixture was poured into water, the aqueous solution was extracted with dichloromethane (twice), and the organic was washed alternately with brine and water (twice). The organics were combined, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated. The product was treated with HCl (3 ml of a 1M solution in diethyl ether) to give the title product (44 mgs, 37%). M ⁺ −H = 356
¹ H NMR (hydrochloride) δ (d ⁶ DMSO, 400 MHz) 1.093 (3H, t), 1.221 (2H, m), 1.542 (2H, m) 1.887 (2H, m) 2.108 (3H, d) 2.333 (3H , s) 2.782 (2H, m), 3.202 (4H, m) 3.473 (4H, m) 4.542 (1H, m) 6.805 (1H, d) 6.871 (1H, d) 7.345 (1H, s), 10.00 (1H , br), 10.80 (1H, s)

（Ｅ４）
室温にて、ジクロロメタン（１０ｍｌ）中、（２−アミノ−５−メチルフェニル）｛１−［シス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝アミン（Ｄ１７、１４７ｍｇ、０．４ｍｍｏｌ）の溶液に、ジイソプロピルエチルアミン（０．０９ｍｌ、１．５当量、０．７ｍｍｏｌ）を加えた。この混合物を０℃まで冷却し、アルゴン下、ビス（トリクロロメチル）カーボネート（０．０５３ｇ、０．４当量、０．２ｍｍｏｌ）を加えた。３０分後、水を加え、この水溶液をジクロロメタンで抽出し（２回）、有機液をブラインおよび水で交互に洗浄した（２回）。有機液を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させた。生成物をＨＣｌ（ジエチルエーテル中１Ｍ溶液３ｍｌ）で処理した。生成物をクロマトグラフィー（ＥｔＯＡｃ ６０％：ヘキサン）、ＳＣＸ、次いでアセトニトリル／水／０／１％ギ酸で溶出するＷａｔｅｒｓ Ｘｂｒｉｄｇｅクロマトグラフィーカラムによりさらに精製し、標題生成物を得た（３３ｍｇｓ、２１％）。Ｍ^＋−Ｈ＝３５８
¹H NMR (塩酸塩)δ(d⁶DMSO 400MHz): 1.129 (3H, t), 1.441 (2H, t), 1.689 (2H, q), 1.887 (4H, t), 1.982 (2H, d), 2.331 (3H, s), 2.828 (2H, m), 3.247 (3H, m), 3.427 (2H, q), 3.492 (3H, m), 4.555 (1H, m), 6.801 (1H, d), 6.870 (1H, d), 7.462 (1H, s), 10.3 (1H, br s), 10.8 (1H, s) Example 4.1 1- {1- [cis-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6-methyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E4)

(E4)
A solution of (2-amino-5-methylphenyl) {1- [cis-4- (ethyloxy) cyclohexyl] -4-piperidinyl} amine (D17, 147 mg, 0.4 mmol) in dichloromethane (10 ml) at room temperature Was added diisopropylethylamine (0.09 ml, 1.5 eq, 0.7 mmol). The mixture was cooled to 0 ° C. and bis (trichloromethyl) carbonate (0.053 g, 0.4 eq, 0.2 mmol) was added under argon. After 30 minutes, water was added, the aqueous solution was extracted with dichloromethane (twice) and the organic was washed alternately with brine and water (twice). The organics were combined, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated. The product was treated with HCl (3 ml of a 1M solution in diethyl ether). The product was further purified by Waters Xbridge chromatography column eluting with chromatography (EtOAc 60%: hexane), SCX, then acetonitrile / water / 0/1% formic acid to give the title product (33 mgs, 21%) . M ⁺ −H = 358
¹ H NMR (hydrochloride) δ (d ⁶ DMSO 400MHz): 1.129 (3H, t), 1.441 (2H, t), 1.689 (2H, q), 1.887 (4H, t), 1.982 (2H, d), 2.331 (3H, s), 2.828 (2H, m), 3.247 (3H, m), 3.427 (2H, q), 3.492 (3H, m), 4.555 (1H, m), 6.801 (1H, d), 6.870 (1H, d), 7.462 (1H, s), 10.3 (1H, br s), 10.8 (1H, s)

（Ｅ５）
０℃にてアルゴン下、ジクロロメタン（３５ｍｌ）中、（２−アミノ−５−メチルフェニル）｛１−［シス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジニル｝アミン（Ｄ２３、４００ｍｇ、１．１５ｍｍｏｌ）およびジイソプロピルエチルアミン（０．２５ｍｌ、１．４ｍｍｏｌ、１．５当量）の攪拌溶液を固体トリホスゲン（１３８ｍｇ、０．４６ｍｍｏｌ、０．４当量）で処理し、室温で３日間維持した（６４％変換）。この混合物を水（２０ｍｌ）で処理し、ジクロロメタンで抽出した（２×２０ｍｌ）。合わせた抽出液をＭｇＳＯ_４で乾燥させ、真空濃縮してベージュ色の固体を得、これをシリカカラム（粗物質２００ｍｇに対してシリカ４０ｇ：メタノール／ジクロロメタン中５％〜１５％０．４Ｍ ＮＨ_３ １２ＣＶ）でのクロマトグラフィーに付し、１５０ｍｇ（収率３５％）の標題化合物を得た。¹H NMR (遊離塩基)δ(CDCl₃ 400MHz): 0.9 (3H, t), 1.4 (2H, m), 1.6 (6H, m), 1.7 (2H, m), 1.85 (2H, m), 2.0 (2H, m), 2.4 (6H, m), 3.1 (2H, m), 3.35 (2H, t), 3.5 (1H, s), 4.3-4.4 (1H, m), 6.85 (1H, d), 6.9 (1H, d), 7.15 (1H, s), 8.3 (1H, s)
MH⁺ 372および373 Example 5. 6-Methyl-1- {1- [cis-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one (E5)

(E5)
(2-Amino-5-methylphenyl) {1- [cis-4- (propyloxy) cyclohexyl] -4-piperidinyl} amine (D23, 400 mg, 1. g) in dichloromethane (35 ml) under argon at 0 ° C. 15 mmol) and diisopropylethylamine (0.25 ml, 1.4 mmol, 1.5 eq) were treated with solid triphosgene (138 mg, 0.46 mmol, 0.4 eq) and maintained at room temperature for 3 days (64% conversion). The mixture was treated with water (20 ml) and extracted with dichloromethane (2 × 20 ml). The combined extracts were dried over MgSO ₄ and concentrated in vacuo to give a beige solid which was purified on a silica column (40 g silica to 200 mg crude material: 5% to 15% 0.4 M NH _{3 in} methanol / dichloromethane. 12CV) to give 150 mg (35% yield) of the title compound. ¹ H NMR (free base) δ (CDCl ₃ 400 MHz): 0.9 (3H, t), 1.4 (2H, m), 1.6 (6H, m), 1.7 (2H, m), 1.85 (2H, m), 2.0 (2H, m), 2.4 (6H, m), 3.1 (2H, m), 3.35 (2H, t), 3.5 (1H, s), 4.3-4.4 (1H, m), 6.85 (1H, d), 6.9 (1H, d), 7.15 (1H, s), 8.3 (1H, s)
MH ⁺ 372 and 373

（Ｅ６）
０℃にてアルゴン下、ジクロロメタン（２０ｍｌ）中、（２−アミノ−５−メチルフェニル）｛１−［トランス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジニル｝アミン（Ｄ２４、３１０ｍｇ、０．８９ｍｍｏｌ）およびジイソプロピルエチルアミン（０．２３ｍｌ、０．３６ｍｍｏｌ、１．５当量）の攪拌溶液を固体トリホスゲン（１０７ｍｇ，０．４当量）で処理し、０℃で３０分間維持した。この混合物を水で処理し、ジクロロメタンで抽出した。合わせた抽出液をＭｇＳＯ_４で乾燥させ、真空濃縮し、３３０ｍｇの標題化合物を褐色固体として得た。この材料をジクロロメタンに溶解し、１Ｍ ＨＣｌ／ジエチルエーテル（５ｍｌ）で処理し、真空濃縮し、塩酸塩を白色固体として得た（３６０ｇ、収率９９％）。
¹H NMR (塩酸塩)δ(CD₃OD 400MHz): 0.95 (3H, t), 1.3-1.4 (2H, m), 1.5-1.7 (4H, m), 2.05 -2.3 (6H, m), 2.4 (3H, m), 2.75-2.9 (2H, m), 3.25-3.4 (4H, m), 3.45 (2H, t), 3.6-3.7 (2H, m), 4.5-4.6 (1H, m), 6.9 (2H, m), 7.15 (1H, m)
MH⁺ 372 and 373 Example 6. 6-Methyl-1- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E6)

(E6)
(2-amino-5-methylphenyl) {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} amine (D24, 310 mg,. 89 mmol) and diisopropylethylamine (0.23 ml, 0.36 mmol, 1.5 eq) were treated with solid triphosgene (107 mg, 0.4 eq) and maintained at 0 ° C. for 30 min. The mixture was treated with water and extracted with dichloromethane. The combined extracts were dried over MgSO ₄ and concentrated in vacuo to give 330 mg of the title compound as a brown solid. This material was dissolved in dichloromethane, treated with 1M HCl / diethyl ether (5 ml) and concentrated in vacuo to give the hydrochloride salt as a white solid (360 g, 99% yield).
¹ H NMR (hydrochloride) δ (CD ₃ OD 400 MHz): 0.95 (3H, t), 1.3-1.4 (2H, m), 1.5-1.7 (4H, m), 2.05 -2.3 (6H, m), 2.4 (3H, m), 2.75-2.9 (2H, m), 3.25-3.4 (4H, m), 3.45 (2H, t), 3.6-3.7 (2H, m), 4.5-4.6 (1H, m), 6.9 (2H, m), 7.15 (1H, m)
MH ⁺ 372 and 373

（Ｅ７）
０℃にてアルゴン下、ジクロロメタン（１５ｍｌ）中、（２−アミノ−５−メチルフェニル）（１−｛トランス−４−［（１−メチルエチル）オキシ］シクロヘキシル｝−４−ピペリジニル）アミン（Ｄ３１、１８７ｍｇ、０．５４ｍｍｏｌ）およびジイソプロピルエチルアミン（０．１４４ｍｌ、０．８１ｍｍｏｌ）の攪拌溶液を固体トリホスゲン（６４ｍｇ、０．２２ｍｍｏｌ）で処理し、０℃で４５分間維持した。この混合物を水（１０ｍｌ）、次いで希ＮａＨＣＯ_３溶液（１５ｍｌ）で処理し、ジクロロメタンで抽出した（２×２０ｍｌ）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残渣を１：１酢酸エチル／ジエチルエーテル（８ｍｌ）でトリチュレートして白色固体を得、１５分後にこれを濾別し、冷１：１酢酸エチル／ジエチルエーテルで洗浄し、真空下、５０℃で乾燥させ、白色固体を得た。この材料をジクロロメタン（２ｍｌ）およびメタノール（０．３ｍｌ）に溶解し、１Ｍ ＨＣｌ／ジエチルエーテル（０．６０ｍｌ）で処理し、真空濃縮した。残渣をジエチルエーテル（５ｍｌ）でトリチュレートして白色固体を得、これを濾別し、ジエチルエーテルで洗浄し、乾燥させ、標題化合物を白色固体として得た。
¹H NMR (塩酸塩)δ(d⁶DMSO, 400 MHz): 1.07 (6H, d), 1.12-1.28 (2H, m), 1.48-1.63 (2H, m), 1.78-1.90 (2H, m), 1.97-2.08 (2H, m), 2.10-2.20 (2H, m), 2.32 (3H, s), 2.82-3.00 (2H, m), 3.12-3.35 (4H, m), 3.42-3.55 (2H, m), 3.62-3.75 (1H, m), 4.50-4.65 (1H, m), 6.79 (1H, d), 6.86 (1H, d), 7.61 (1H, s), 10.78 (1H, s), 10.85 (1H, br s) Example 7. 6-Methyl-1- (1- {trans-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloric acid Salt (E7)

(E7)
(2-Amino-5-methylphenyl) (1- {trans-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) amine (D31) in dichloromethane (15 ml) under argon at 0 ° C. , 187 mg, 0.54 mmol) and diisopropylethylamine (0.144 ml, 0.81 mmol) were treated with solid triphosgene (64 mg, 0.22 mmol) and maintained at 0 ° C. for 45 min. The mixture was treated with water (10 ml) then dilute NaHCO ₃ solution (15 ml) and extracted with dichloromethane (2 × 20 ml). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was triturated with 1: 1 ethyl acetate / diethyl ether (8 ml) to give a white solid which was filtered off after 15 minutes and washed with cold 1: 1 ethyl acetate / diethyl ether at 50 ° C. under vacuum. Drying gave a white solid. This material was dissolved in dichloromethane (2 ml) and methanol (0.3 ml), treated with 1M HCl / diethyl ether (0.60 ml) and concentrated in vacuo. The residue was triturated with diethyl ether (5 ml) to give a white solid which was filtered off, washed with diethyl ether and dried to give the title compound as a white solid.
¹ H NMR (hydrochloride) δ (d ⁶ DMSO, 400 MHz): 1.07 (6H, d), 1.12-1.28 (2H, m), 1.48-1.63 (2H, m), 1.78-1.90 (2H, m) , 1.97-2.08 (2H, m), 2.10-2.20 (2H, m), 2.32 (3H, s), 2.82-3.00 (2H, m), 3.12-3.35 (4H, m), 3.42-3.55 (2H, m), 3.62-3.75 (1H, m), 4.50-4.65 (1H, m), 6.79 (1H, d), 6.86 (1H, d), 7.61 (1H, s), 10.78 (1H, s), 10.85 (1H, br s)

（Ｅ８）
（２−アミノ−５−メチルフェニル）｛１−［シス−１−メチル−４−（メチルオキシ）シクロヘキシル］−４−ピペリジニル｝アミン（Ｄ３６、９１ｍｇ、０．２７ｍｍｏｌ）をジクロロメタン（５ｍｌ）に溶解し、０℃まで冷却した後、０℃にて、ビス（トリクロロメチル）カーボネート（０．４当量、０．１１ｍｍｏｌ、３１ｍｇ）、次いでヒューニッヒの塩基ジイソプロピルエチルアミン（１．５当量、６８μｌ）を加え、この混合物を同じ温度で１時間攪拌し、その後、ＮａＨＣＯ_３（飽和水溶液）でクエンチした。２層に分け、有機相をＮａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させて粗生成物を得、これをクロマトグラフィー（ＭｅＯＨ−ＮＨ_３−ＤＣＭ）により精製し、標題化合物を得た（７６ｍｇ、８０％、９９．７％＝異性体純度）。次に、ＨＣｌ溶液（ジエチルエーテル中１Ｍ、２当量）を用い、標題化合物を塩酸塩へ変換した。
¹H NMRδ(d⁶DMSO, 400 MHz) 0.851 (3H, s), 1.139 (2H, t), 1.585 (4H, m), 1.669 (2H, d), 1.884 (2H, d), 2.141 (2H, t), 2.262 (2H, t), 2.316 (3H, s), 3.011 (2H, d), 3.241 (3H, s), 4.020 (1H, m br), 6.768 (1H, d), 6.836 (1H, d), 6.994 (1H, s) 10.7 (1H, s br) Example 8. 6-Methyl-1- {1- [cis-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E8)

(E8)
(2-Amino-5-methylphenyl) {1- [cis-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} amine (D36, 91 mg, 0.27 mmol) dissolved in dichloromethane (5 ml) After cooling to 0 ° C., at 0 ° C., bis (trichloromethyl) carbonate (0.4 eq, 0.11 mmol, 31 mg) was added, followed by Hunig's base diisopropylethylamine (1.5 eq, 68 μl), The mixture was stirred at the same temperature for 1 hour and then quenched with NaHCO ₃ (saturated aqueous solution). The two phases were separated and the organic phase was dried over Na ₂ SO ₄ , filtered and the solvent was evaporated to give the crude product, which was purified by chromatography (MeOH—NH ₃ -DCM) to give the title compound. (76 mg, 80%, 99.7% = isomer purity). The title compound was then converted to the hydrochloride salt using HCl solution (1M in diethyl ether, 2 eq).
¹ H NMRδ (d ⁶ DMSO, 400 MHz) 0.851 (3H, s), 1.139 (2H, t), 1.585 (4H, m), 1.669 (2H, d), 1.884 (2H, d), 2.141 (2H, t), 2.262 (2H, t), 2.316 (3H, s), 3.011 (2H, d), 3.241 (3H, s), 4.020 (1H, m br), 6.768 (1H, d), 6.836 (1H, d), 6.994 (1H, s) 10.7 (1H, s br)

（Ｅ９）
（２−アミノ−５−メチルフェニル）｛１−［トランス−１−メチル−４−（メチルオキシ）シクロヘキシル］−４−ピペリジニル｝アミン（Ｄ３７、３０ｍｇ、０．０９１ｍｍｏｌ）をジクロロメタン（２ｍｌ）に溶解し、０℃まで冷却した。次に、０℃にて、ビス（トリクロロメチル）カーボネート（０．４当量、０．０３６ｍｍｏｌ、１１ｍｇ）、次いでヒューニッヒの塩基ジイソプロピルエチルアミン（１．５当量、２３μｌ）を加えた。この混合物を同じ温度で１時間攪拌した後、ＮａＨＣＯ_３（飽和水溶液）でクエンチした。２層に分け、有機相をＮａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させて粗生成物を得、これをクロマトグラフィー（ＭｅＯＨ−ＮＨ_３−ＤＣＭ）により精製し、標題化合物を得た（９ｍｇ、２８％、９７．８％＝異性体純度）。その後、ＨＣｌ溶液（ジエチルエーテル中１Ｍ、２当量）を用い、標題化合物を塩酸塩へ変換した。
¹H NMR δ(d⁶DMSO, 400 MHz) 0.851 (3H, s), 1.503 (6H, m), 1.663 (2H, d br), 1.794 (2H, m br), 2.157 (2H, t), 2.272 (2H, t), 2.320 (3H, s), 3.045 (2H, d), 3.161 (3H, s), 4.027 (1H, m br), 6.768 (1H, d), 6.836 (1H, d), 7.000 (1H, s), 10.7 (1H, s br) Example 9. 6-Methyl-1- {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E9)

(E9)
(2-Amino-5-methylphenyl) {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} amine (D37, 30 mg, 0.091 mmol) dissolved in dichloromethane (2 ml) And cooled to 0 ° C. Next, at 0 ° C., bis (trichloromethyl) carbonate (0.4 eq, 0.036 mmol, 11 mg) was added followed by Hunig's base diisopropylethylamine (1.5 eq, 23 μl). The mixture was stirred at the same temperature for 1 hour and then quenched with NaHCO ₃ (saturated aqueous solution). The two phases were separated and the organic phase was dried over Na ₂ SO ₄ , filtered and the solvent was evaporated to give the crude product, which was purified by chromatography (MeOH—NH ₃ -DCM) to give the title compound. (9 mg, 28%, 97.8% = isomer purity). The title compound was then converted to the hydrochloride salt using HCl solution (1M in diethyl ether, 2 eq).
¹ H NMR δ (d ⁶ DMSO, 400 MHz) 0.851 (3H, s), 1.503 (6H, m), 1.663 (2H, d br), 1.794 (2H, m br), 2.157 (2H, t), 2.272 (2H, t), 2.320 (3H, s), 3.045 (2H, d), 3.161 (3H, s), 4.027 (1H, m br), 6.768 (1H, d), 6.836 (1H, d), 7.000 (1H, s), 10.7 (1H, s br)

（Ｅ１０）
０℃にてアルゴン下、ジクロロメタン（１５ｍｌ）中、（２−アミノ−５−メチルフェニル）（１−｛シス−４−［（１−メチルエチル）オキシ］シクロヘキシル｝−４−ピペリジニル）アミン（Ｄ３９、１７０ｍｇ、０．４９ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（０．１３ｍｌ、０．７４ｍｍｏｌ）、次いで固体トリホスゲン（５７ｍｇ、０．１９６ｍｍｏｌ）で処理し、０℃で１時間維持した。この混合物を水（１０ｍｌ）、次いで希ＮａＨＣＯ_３溶液（１５ｍｌ）で処理し、ジクロロメタンで抽出した（２×２５ｍｌ）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残渣をジクロロメタン（４ｍｌ）に溶解し、１Ｍ ＨＣｌ／ジエチルエーテル（０．７ｍｌ）で処理し、真空濃縮した。残渣をジエチルエーテル（１０ｍｌ）でトリチュレートして白色固体を得、これを濾別し、ジエチルエーテルで洗浄し、真空下５０℃で乾燥させ、塩酸塩を白色固体として得た（１７０ｍｇ、８５％）。
¹H NMR (塩酸塩) δ(d⁶DMSO, 400 MHz): 1.10 (6H, d), 1.39-1.52 (2H, m), 1.62-1.80 (2H, m), 1.80-2.00 (6H, m), 2.32 (3H, s), 2.82-3.00 (2H, m), 3.18-3.32 (3H, m), 3.40-3.55 (2H, m), 3.55-3.70 (2H, m), 4.50-4.65 (1H, m), 6.80 (1H, d), 6.87 (1H, d), 7.60 (1H, s), 10.73 (1H, br s), 10.80 (1H, s) Example 10.6-Methyl-1- (1- {cis-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloric acid Salt (E10)

(E10)
(2-Amino-5-methylphenyl) (1- {cis-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) amine (D39) in dichloromethane (15 ml) under argon at 0 ° C. , 170 mg, 0.49 mmol) was treated with diisopropylethylamine (0.13 ml, 0.74 mmol) followed by solid triphosgene (57 mg, 0.196 mmol) and maintained at 0 ° C. for 1 hour. The mixture was treated with water (10 ml) then dilute NaHCO ₃ solution (15 ml) and extracted with dichloromethane (2 × 25 ml). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dissolved in dichloromethane (4 ml), treated with 1M HCl / diethyl ether (0.7 ml) and concentrated in vacuo. The residue was triturated with diethyl ether (10 ml) to give a white solid, which was filtered off, washed with diethyl ether and dried under vacuum at 50 ° C. to give the hydrochloride salt as a white solid (170 mg, 85%) .
¹ H NMR (hydrochloride) δ (d ⁶ DMSO, 400 MHz): 1.10 (6H, d), 1.39-1.52 (2H, m), 1.62-1.80 (2H, m), 1.80-2.00 (6H, m) , 2.32 (3H, s), 2.82-3.00 (2H, m), 3.18-3.32 (3H, m), 3.40-3.55 (2H, m), 3.55-3.70 (2H, m), 4.50-4.65 (1H, m), 6.80 (1H, d), 6.87 (1H, d), 7.60 (1H, s), 10.73 (1H, br s), 10.80 (1H, s)

Examples 11 and 12. Cis and trans 1- (1- [4- (ethoxyl) cyclohexyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (cis = E11; trans = E12)

  In a microwave container, 4- (2-oxo-1-benzimidazolinyl) piperidine (0.217 g, 1 mmol), 4-ethoxycyclohexanone (D10, 0.22 g, 1.55 mmol), acetic acid (0.2 ml), Dichloromethane (15 ml) and cyanoborohydride (polystyrylmethyl) trimethylammonium (4.3 meq / g) (750 mg) were heated in a microwave reactor at 110 ° C. for 20 minutes. Further 4-ethoxycyclohexanone (146 mg, 1.0 mmol) and cyanoborohydride (polystyrylmethyl) trimethylammonium (300 mg) were added and the mixture was heated in a microwave reactor at 110 ° C. for an additional 20 minutes. The cooled mixture was filtered under vacuum and the filtrate was loaded onto a 5 g SCX cartridge and eluted with methanol followed by methanolic ammonia. Removal of the solvent from the methanolic ammonia fraction gave 260 mg of a clear oil, which was obtained using a Waters Xbridge chromatography column and a gradient of aqueous ammonium bicarbonate (10 mmol; adjusted to pH 10 with ammonia) and acetonitrile as the mobile phase. Purification gave the cis and trans isomers. When each isomer was obtained, it was redissolved in dichloromethane (2 ml), 1 mol HCl in diethyl ether (0.5 ml) was added, and then the solvent was removed to give the title compound.

An early eluting isomer (trans isomer; E12) was obtained as an off-white solid (0.024 g). MH ⁺ = 344
¹ HNMR δ d ⁶ DMSO, 250 MHz): 1.1-1.4 (assuming 8H, m), 1.65 (assuming 2H, m), 1.8 (2H, m), 2.0 (assuming 2H, m), 2.2-2.4 ( 6H, m), 2.9 (2H, d), 3.1-3.2 (1H, m), 3.4-3.5 (2H, q), 4.0-4.2 (1H, m), 7.0 (Assuming 3H, m), 7.2 (assuming 1H, m)

The slow eluting isomer (cis isomer; E11) was obtained as a white solid (0.026 g). MH + = 344
¹ HNMR δ CDCl3, 250 MHz): 1.29 (assuming 3H, t), 1.25-1.5 (assuming 3H, m), 1.6-2.05 (m), 2.3-2.5 (assuming 5H, m), 3.0-3.1 ( 2H, m), 3.4-3.6 (4H, m assumed), 4.25-4.45 (1H, m assumed), 7.0-7.1 (3H, m assumed), 7.3 (1H, m assumed), 8.05 (Assuming 1H, s)

（Ｅ１３）
０℃にてアルゴン下、ジクロロメタン（１０ｍｌ）中、Ｎ^２−｛１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝−４−フルオロ−１，２−ベンゼンジアミン（Ｄ７２、＜０．３３ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（０．０８７ｍｌ、０．４９ｍｍｏｌ）で処理した後、固体トリホスゲン（３８ｍｇ、０．１３ｍｍｏｌ）を加え、３０分間維持した。この混合物を希ＮａＨＣＯ_３溶液（１０ｍｌ）で処理し、ジクロロメタンで抽出した（２×２０ｍｌ）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮してベージュ色の固体を得、これをＥｔＯＡｃ／Ｅｔ２Ｏから再結晶させ、標題化合物の遊離塩基を白色固体として得た（９０ｍｇ、＞７６％）。これをジクロロメタン（２ｍｌ）に溶解し、１Ｍ ＨＣｌ／Ｅｔ_２Ｏ（０．３０ｍｌ）で処理し、アルゴン気流下で濃縮し、標題化合物を白色固体として得た。ＭＨ^＋＝３６２
¹H NMR (遊離塩基) δ (CDCl₃, 400MHz): 1.15-1.42 (7H, t + mと仮定), 1.82 (2H, br m), 1.92 (2H, br m), 2.12 (2H, br m), 2.30-2.50 (5H, m), 3.10-3.13 (2H, m), 3.13-3.35 (1H, m), 3.52 (2H, q), 4.25-4.40 (1H, m), 6.73-6.80 (1H, m), 6.96-7.02 (1H, m), 7.05 (1H, br d), 9.83 (1H, s) Example 13. 1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6-fluoro-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E13)

(E13)
Under argon at 0 ° C., in dichloromethane ^{(10ml), N 2 - {} 1- [ trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -4-fluoro-1,2-benzenediamine (D72, <0 After stirring a stirred solution of .33 mmol) with diisopropylethylamine (0.087 ml, 0.49 mmol), solid triphosgene (38 mg, 0.13 mmol) was added and maintained for 30 minutes. The mixture was treated with dilute NaHCO ₃ solution (10 ml) and extracted with dichloromethane (2 × 20 ml). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a beige solid that was recrystallized from EtOAc / Et 2 O to give the free base of the title compound as a white solid (90 mg,> 76%). This was dissolved in dichloromethane (2 ml), treated with 1M HCl / Et ₂ O (0.30 ml) and concentrated under a stream of argon to give the title compound as a white solid. MH ⁺ = 362
¹ H NMR (free base) δ (CDCl ₃ , 400 MHz): 1.15-1.42 (assuming 7H, t + m), 1.82 (2H, br m), 1.92 (2H, br m), 2.12 (2H, br m ), 2.30-2.50 (5H, m), 3.10-3.13 (2H, m), 3.13-3.35 (1H, m), 3.52 (2H, q), 4.25-4.40 (1H, m), 6.73-6.80 (1H , m), 6.96-7.02 (1H, m), 7.05 (1H, br d), 9.83 (1H, s)

（Ｅ１４）
０℃にて、ジクロロメタン（５０ｍｌ）中、４−ブロモ−Ｎ^２−｛１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝−１，２−ベンゼンジアミン（Ｄ７４、６００ｍｇ、１．５ｍｍｏｌ）およびジイソプロピルエチルアミン（０．４ｍｌ、２．２５ｍｍｏｌ）の攪拌溶液をトリホスゲン（１７８ｍｇ、０．６ｍｍｏｌ）で処理し、３０分間攪拌した。この混合物を水で洗浄し、飽和ＮａＨＣＯ_３溶液、次いでジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮して白色固体を得、これを１０％Ｅｔ_２Ｏ／石油エーテルで洗浄し、標題化合物の遊離塩基を白色固体として得た（４２６ｍｇ、６７％）。この一部（２２６ｍｇ）をジクロロメタン（１０ｍｌ）に溶解し、１Ｍ ＨＣｌ／Ｅｔ_２Ｏ（５ｍｌ）で処理し、３０分間攪拌した後、真空濃縮し、標題化合物を白色固体として得た（２２０ｍｇ）。ＭＨ＋＝４２３、４２４
¹H NMR δ(d^６DMSO, 400MHz): 1.09 (3H, t), 1.12-1.30 (2H, m), 1.48-1.62 (2H, m), 1.90 (2H, br d), 2.05-2.18 (4H, m), 2.70-2.85 (2H, m), 3.15-3.30 (4H, m), 3.41-3.55 (4H, m), 4.53-4.65 (1H, m), 6.95 (1H, d), 7.16 (1H, dd), 7.66 (1H, d), 10.35 (1H, br m), 11.11 (1H, s) Example 14. 6-Bromo-1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E14)

(E14)
At 0 ° C., in dichloromethane (50 ml), 4-bromo ^-N 2 - {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D74,600mg, 1. A stirred solution of 5 mmol) and diisopropylethylamine (0.4 ml, 2.25 mmol) was treated with triphosgene (178 mg, 0.6 mmol) and stirred for 30 minutes. The mixture was washed with water and extracted with saturated NaHCO ₃ solution and then dichloromethane. The extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a white solid which was washed with 10% Et ₂ O / petroleum ether to give the free base of the title compound as a white solid (426 mg, 67 %). A portion of this (226 mg) was dissolved in dichloromethane (10 ml), treated with 1M HCl / Et ₂ O (5 ml), stirred for 30 minutes then concentrated in vacuo to give the title compound as a white solid (220 mg). MH + = 423, 424
¹ H NMR δ (d ⁶ DMSO, 400 MHz): 1.09 (3H, t), 1.12-1.30 (2H, m), 1.48-1.62 (2H, m), 1.90 (2H, br d), 2.05-2.18 (4H , m), 2.70-2.85 (2H, m), 3.15-3.30 (4H, m), 3.41-3.55 (4H, m), 4.53-4.65 (1H, m), 6.95 (1H, d), 7.16 (1H , dd), 7.66 (1H, d), 10.35 (1H, br m), 11.11 (1H, s)

（Ｅ１５）
ジクロロエタン（５ｍｌ）中、１−（４−ピペリジニル）−６−（トリフルオロメチル）−１，３−ジヒドロ−２Ｈ−ベンズイミダゾール−２−オン（Ｄ１４１、０．６３ｍｍｏｌ、１８０ｍｇ）の溶液に、４−（エチルオキシ）シクロヘキサノン（Ｄ１０、４当量、２．５２ｍｍｏｌ、３５８ｍｇ）、Ｅｔ_３Ｎ（数滴）および５Ａモレキュラーシーブスを加えた。この反応物を一晩攪拌した。ＮａＢＨ（ＯＡｃ）_３（１．５当量、０．９４６４ｍｍｏｌ、０．２ｇ）を加え、この反応物を４晩攪拌した。この混合物を２Ｍ ＮａＯＨ（１ｍｌ）で塩基化した。反応物をＮａＨＣＯ_３でクエンチし、この水溶液をジクロロメタンで抽出した。有機液を合わせ、水で洗浄し（２×５０ｍｌ）、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させ、粗生成物を得た。粗生成物をシリカカラムでのクロマトグラフィー（１０％ＭｅＯＨ／ジクロロメタン）、次いでＢｉｏｔａｇｅ ＫＰ−ＮＨ（商標）−シリカカラムでの別のカラムクロマトグラフィー（ｎｈｅｘ中１１％〜１３％ＥｔＯＡｃ）により精製し、標題化合物の遊離塩基を得た（２３ｍｇ、９％）。Ｍ^＋＋Ｈ＝４１２。次に、ＨＣｌ溶液（Ｅｔ_２Ｏ中１Ｍ）を用い、これを標題化合物へ変換し、２３ｍｇを得た。
¹H NMR δ(d⁶DMSO, 400MHz) 1.111 (3H, t), 1.397 (2H, m), 1.694 (2H, q), 1.937 (6H, m), 2.782 (2H q), 3.240 (3H, m), 3.404 (2H, q), 3.536 (3H, m), 4.626 (1H m), 7.172 (1H, d), 7.373 (1H, d), 7.707 (1H, s), 10.05 (1H, s br), 11.45 (1H, s) Example 15. 1- {1- [cis-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6- (trifluoromethyl) -1,3-dihydro-2H-benzimidazol-2-one monohydrochloride (E15)

(E15)
To a solution of 1- (4-piperidinyl) -6- (trifluoromethyl) -1,3-dihydro-2H-benzimidazol-2-one (D141, 0.63 mmol, 180 mg) in dichloroethane (5 ml) was added 4 - (ethyloxy) cyclohexanone was added (D10,4 _{eq, 2.52mmol, 358mg), Et 3} N ( few drops) and 5A molecular sieves. The reaction was stirred overnight. NaBH (OAc) ₃ (1.5 eq, 0.9464 mmol, 0.2 g) was added and the reaction was stirred for 4 nights. The mixture was basified with 2M NaOH (1 ml). The reaction was quenched with NaHCO ₃ and the aqueous solution was extracted with dichloromethane. The organics were combined, washed with water (2 × 50 ml), dried over Na ₂ SO ₄ , filtered and the solvent was evaporated to give the crude product. The crude product was purified by chromatography on a silica column (10% MeOH / dichloromethane) followed by another column chromatography on a Biotage KP-NH ™ -silica column (11% to 13% EtOAc in nhex) The free base of the title compound was obtained (23 mg, 9%). M ⁺⁺ H = 412. This was then converted to the title compound using HCl solution (1M in Et ₂ O) to give 23 mg.
¹ H NMR δ (d ⁶ DMSO, 400MHz) 1.111 (3H, t), 1.397 (2H, m), 1.694 (2H, q), 1.937 (6H, m), 2.782 (2H q), 3.240 (3H, m ), 3.404 (2H, q), 3.536 (3H, m), 4.626 (1H m), 7.172 (1H, d), 7.373 (1H, d), 7.707 (1H, s), 10.05 (1H, s br) , 11.45 (1H, s)

（Ｅ１６）
０℃にて、ジクロロメタン（２５ｍｌ）中、４−エチル−Ｎ^２−｛１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝−１，２−ベンゼンジアミン（Ｄ７６、３４８ｍｇ、１ｍｍｏｌ）およびジイソプロピルエチルアミン（０．１７ｍｌ、１．５ｍｍｏｌ）の攪拌溶液をトリホスゲン（１１８ｍｇ、０．４ｍｍｏｌ）で処理し、０℃で３０分間攪拌した。この混合物を水で洗浄し、飽和ＮａＨＣＯ_３溶液、次いでジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、淡黄色固体を得た。これをジクロロメタン（５ｍｌ）に溶解し、ＨＣｌ／Ｅｔ_２Ｏ（３ｍｌ）で処理し、真空濃縮し、標題化合物を白色固体として得た（２６０ｍｇ、６５％）。ＭＨ＋＝３７２
¹H NMR δ(d⁶DMSO, 400MHz): 1.05-1.33 (2H, m), 1.10 (3H, t), 1.21 (3H, t), 1.47-1.63 (2H, m), 1.85 (2H, br d), 2.05-2.25 (4H, m), 2.50-2.68 (2H, m), 2.80-3.00 (2H, m), 3.13-3.30 (4H, m), 3.35-3.55 (4H, m), 4.50-4.62 (1H, m), 6.80-6.90 (2H, m), 7.54 (1H, s), 10.7 (1H, br m), 10.80 (1H, s) Example 16 6-Ethyl-1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E16)

(E16)
At 0 ° C., in dichloromethane (25 ml), 4-ethyl ^-N 2 - {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D76,348mg, 1mmol) And a stirred solution of diisopropylethylamine (0.17 ml, 1.5 mmol) was treated with triphosgene (118 mg, 0.4 mmol) and stirred at 0 ° C. for 30 minutes. The mixture was washed with water and extracted with saturated NaHCO ₃ solution and then dichloromethane. The extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a pale yellow solid. This was dissolved in dichloromethane (5 ml), treated with HCl / Et ₂ O (3 ml) and concentrated in vacuo to give the title compound as a white solid (260 mg, 65%). MH + = 372
¹ H NMR δ (d ⁶ DMSO, 400MHz): 1.05-1.33 (2H, m), 1.10 (3H, t), 1.21 (3H, t), 1.47-1.63 (2H, m), 1.85 (2H, br d ), 2.05-2.25 (4H, m), 2.50-2.68 (2H, m), 2.80-3.00 (2H, m), 3.13-3.30 (4H, m), 3.35-3.55 (4H, m), 4.50-4.62 (1H, m), 6.80-6.90 (2H, m), 7.54 (1H, s), 10.7 (1H, br m), 10.80 (1H, s)

（Ｅ１７）
０℃にて、ジクロロメタン（２０ｍｌ）中、４−シクロプロピル−Ｎ^２−｛１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝−１，２−ベンゼンジアミン（Ｄ７８、２００ｍｇ、０．５６ｍｍｏｌ）およびジイソプロピルエチルアミン（０．１４ｍｌ、０．８４ｍｍｏｌ）の攪拌溶液をトリホスゲン（６６ｍｇ、０．２３ｍｍｏｌ）で処理し、０℃で３０分間攪拌した。この溶液を水および飽和ＮａＨＣＯ_３溶液で洗浄した後、ジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残渣をジクロロメタン（１０ｍｌ）に溶解し、１Ｍ ＨＣｌ／Ｅｔ_２Ｏ（３ｍｌ）で処理し、３０分間攪拌した後、真空濃縮し、標題化合物を白色固体として得た（１６５ｍｇ、７２％）。ＭＨ＋＝３８４
¹H NMR δ(d⁶DMSO, 400MHz): 0.70-0.77 (2H, m), 0.84-0.94 (2H, m), 1.09 (3H, t), 1.10-1.30 (2H, m), 1.48-1.62 (2H, m), 1.85 (2H, br d), 1.88-2.00 (1H, m), 2.04-2.20 (4H, m), 2.78-2.95 (2H, m), 3.15-3.30 (4H, m), 3.40-3.55 (4H, m), 4.50-4.62 (1H, m), 6.71 (1H, d), 6.85 (1H, d), 7.28 (1H, s), 10.6 (1H, br m), 10.78 (1H, s) Example 17 6-Cyclopropyl-1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E17)

(E17)
At 0 ° C., in dichloromethane (20 ml), ^{4-cyclopropyl--N} 2 - {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D78,200mg, 0 .56 mmol) and a diisopropylethylamine (0.14 ml, 0.84 mmol) stirred solution was treated with triphosgene (66 mg, 0.23 mmol) and stirred at 0 ° C. for 30 min. The solution was washed with water and saturated NaHCO ₃ solution and then extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dissolved in dichloromethane (10 ml), treated with 1M HCl / Et ₂ O (3 ml), stirred for 30 minutes then concentrated in vacuo to give the title compound as a white solid (165 mg, 72%). MH + = 384
¹ H NMR δ (d ⁶ DMSO, 400MHz): 0.70-0.77 (2H, m), 0.84-0.94 (2H, m), 1.09 (3H, t), 1.10-1.30 (2H, m), 1.48-1.62 ( 2H, m), 1.85 (2H, br d), 1.88-2.00 (1H, m), 2.04-2.20 (4H, m), 2.78-2.95 (2H, m), 3.15-3.30 (4H, m), 3.40 -3.55 (4H, m), 4.50-4.62 (1H, m), 6.71 (1H, d), 6.85 (1H, d), 7.28 (1H, s), 10.6 (1H, br m), 10.78 (1H, s)

（Ｅ１８）
０℃にてアルゴン下、ジクロロメタン（１０ｍｌ）中、Ｎ^２−｛１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝−４−（メチルオキシ）−１，２−ベンゼンジアミン（Ｄ８０、１２０ｍｇ、０．３５ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（０．０９２ｍｌ、０．５２ｍｍｏｌ）で処理した後、固体トリホスゲン（４０ｍｇ、０．１４ｍｍｏｌ）を加え、３０分間維持した。この混合物を１０％Ｎａ_２ＣＯ_３溶液（１０ｍｌ）で処理し、ジクロロメタンで抽出した（２×１５ｍｌ）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮してベージュ色の固体を得、これを１：１ ＥｔＯＡｃ／Ｅｔ_２Ｏから再結晶させ、標題化合物の遊離塩基を白色固体として得た（１０５ｍｇ、８１％）。これをジクロロメタン（５ｍｌ）に溶解し、１Ｍ ＨＣｌ／Ｅｔ_２Ｏ（０．３ｍｌ）で処理し、真空濃縮し、標題化合物を白色固体として得た（１１０ｍｇ）。ＭＨ^＋＝３７４
¹H NMR δ(d⁶DMSO, 400MHz): 1.07 (3H, t), 1.10-1.30 (4H, m), 1.47-1.67 (2H, m), 1.80-1.92 (2H, m), 2.03-2.23 (4H, m), 2.80-3.00 (2H, m), 3.12-3.32 (4H, m), 3.40-3.65 (2Hと仮定), 3.79 (3H, s), 4.50-4.67 (1H, m), 6.58 (1H, d), 6.87 (1H, d), 7.26 (1H, s), 10.71 (1H, s), 10.8 (1H, br m) Example 18. 1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6- (methyloxy) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E18 )

(E18)
Under argon at 0 ° C., in dichloromethane ^{(10ml), N 2 - {} 1- [ trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -4- (methyloxy) -1,2-benzenediamine (D80 , 120 mg, 0.35 mmol) was treated with diisopropylethylamine (0.092 ml, 0.52 mmol), then solid triphosgene (40 mg, 0.14 mmol) was added and maintained for 30 minutes. The mixture was treated with 10% Na ₂ CO ₃ solution (10 ml) and extracted with dichloromethane (2 × 15 ml). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a beige solid that was recrystallized from 1: 1 EtOAc / Et ₂ O to give the free base of the title compound as a white solid. (105 mg, 81%). This was dissolved in dichloromethane (5 ml), treated with 1M HCl / Et ₂ O (0.3 ml) and concentrated in vacuo to give the title compound as a white solid (110 mg). MH ⁺ = 374
¹ H NMR δ (d ⁶ DMSO, 400MHz): 1.07 (3H, t), 1.10-1.30 (4H, m), 1.47-1.67 (2H, m), 1.80-1.92 (2H, m), 2.03-2.23 ( 4H, m), 2.80-3.00 (2H, m), 3.12-3.32 (4H, m), 3.40-3.65 (assuming 2H), 3.79 (3H, s), 4.50-4.67 (1H, m), 6.58 ( 1H, d), 6.87 (1H, d), 7.26 (1H, s), 10.71 (1H, s), 10.8 (1H, br m)

Examples 19 and 20. Cis and trans-1- {1- [4- (ethoxy) cyclohexyl] -4-piperidinyl} -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one (cis = E19; Transformer = E20)

  In a microwave container, 1- (4-piperidinyl) -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one (D83, 337 mg), 4- (ethoxy) cyclohexanone ( D10, 190 mg) Cyanoborohydride (polystyrylmethyl) trimethylammonium (4.3 meq / g 0.6 g), sodium acetate (100 mg), dichloromethane (10 ml), acetic acid (200 μl), microwave reactor And heated at 110 ° C. for 20 minutes. Additional 4- (ethoxy) cyclohexanone (D10, 0.06 g) and cyanoborohydride (polystyrylmethyl) trimethylammonium (4.3 meq / g 0.6 g) were added and at 110 ° C. in a microwave reactor. Heated for 20 minutes. The cooled mixture was filtered and the filtrate was loaded onto an SCX cartridge and eluted with methanol followed by methanolic ammonia. The methanolic ammonia fraction was evaporated and the resulting mixture was purified using a Waters Xbridge chromatography column. Cis and trans isomers were obtained using a gradient of aqueous ammonium bicarbonate (adjusted to pH 10 with 10 mmol ammonia) and acetonitrile as the mobile phase. Once obtained, each isomer was redissolved in dichloromethane (2 ml), 1 mol HCl in diethyl ether (0.5 ml) was added, and then the solvent was removed.

The fast eluting isomer (trans isomer E20) was obtained as a white solid (0.035 g). MH ⁺ =. 428
¹ H NMR δ (DMSO, 250 MHz): 1.1 (3H, t), 1.1-1.3 (2H, m), 1.4-1.7 (2H, m), 1.8-2.0 (2H, m), 2.0-2.2 (4H , m), 2.7-2.9 (2H, m), 3.1-3.4 (4H, m), 3.4-3.6 (4H, m), 4.5-4.7 (1H, br m), 6.95-7.1 (2H, m), 7.15 (1H, s), 10.4 (1H, br), 11.2 (1H, s)

The slow eluting isomer (cis isomer E19) was obtained as a white solid (0.015 g). MH ⁺ = 428
¹ H NMR δ (DMSO, 250 MHz): 1.1 (3H, t), 1.35-1.5 (2H, m), 1.6-1.8 (2H, m), 1.8-2.1 (6H, m), 2.6-2.8 (2H , m), 3.1-3.6 (obs, m), 4.5-4.7 (1H, m), 7.0-7.1 (2H, m), 7.5 (1H, s), 9.6-9.8 (1H, br), 11.2 (1H , s)

（Ｅ２１）
８−［（トリフルオロメチル）オキシ］−１，４−ジオキサスピロ［４．５］デカン（Ｄ８５、４００ｍｇ）、ＴＨＦ（５ｍｌ）および５Ｍ塩酸水溶液（５ｍｌ）の混合物を室温で２時間攪拌した後、ジクロロメタン／水で分液した。次に、有機層を乾燥させ、蒸発させ、粗ケトンを得た。この粗ケトンを１−（４−ピペリジニル）−６−メチル−１，３−ジヒドロ−２Ｈ−ベンズイミダゾール−２−オン（Ｄ１４５、１１０ｍｇ、０．５ｍｍｏｌ）、シアノ水素化ホウ素（ポリスチリルメチル）トリメチルアンモニウム（２．０４ｍｍｏｌ／ｇ６００ｍｇ、１．２５ｍｍｏｌ）、ジクロロメタン（２．５ｍｌ）および酢酸（０．１５ｍｌ、２．５ｍｍｏｌ）と合わせ、マイクロ波反応装置にて１１０℃で１０分間加熱した。冷却混合物を濾過し、濾液をＳＣＸカートリッジに乗せ、メタノール、次いでメタノール性アンモニアで溶出した。メタノール性アンモニア画分を蒸発させ、得られた混合物を、Ｗａｔｅｒｓ Ｘｂｒｉｄｇｅクロマトグラフィーカラムを用いて精製した。アンモニアでｐＨ１０に調整した重炭酸アンモニウム水溶液（１０ｍｍｏｌ）とアセトニトリルの勾配を移動相として用い、標題化合物を得、これを塩酸塩へ変換し、ジエチルエーテルから異性体混合物として結晶化させた（４２ｍｇ）。
1HNMR (塩酸塩) δ(d⁶DMSO): 1.5-2.2 (9H, m), 2.35 (3H, s), 2.8 (2H, m), 3.2-3.6 (11H, m), 4.4 (0.4H, m), 4.55 (1H, m), 4.7 (0.6H,br s), 6.8-6.9 (2H, m), 7.5 (1H, 2s), 10.55 (0.6H, br s), 10.7 (0.4H, br s), 10.8 (1H, 2s), MH+ 398 Example 21. Cis / trans-6-methyl-1- [1- (4-trifluoromethoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E21)

(E21)
After stirring a mixture of 8-[(trifluoromethyl) oxy] -1,4-dioxaspiro [4.5] decane (D85, 400 mg), THF (5 ml) and 5M aqueous hydrochloric acid (5 ml) at room temperature for 2 hours, Partitioned with dichloromethane / water. The organic layer was then dried and evaporated to give the crude ketone. This crude ketone was converted to 1- (4-piperidinyl) -6-methyl-1,3-dihydro-2H-benzimidazol-2-one (D145, 110 mg, 0.5 mmol), cyanoborohydride (polystyrylmethyl) trimethyl. Combined with ammonium (2.04 mmol / g 600 mg, 1.25 mmol), dichloromethane (2.5 ml) and acetic acid (0.15 ml, 2.5 mmol) and heated in a microwave reactor at 110 ° C. for 10 minutes. The cooled mixture was filtered and the filtrate was loaded onto an SCX cartridge and eluted with methanol followed by methanolic ammonia. The methanolic ammonia fraction was evaporated and the resulting mixture was purified using a Waters Xbridge chromatography column. A gradient of aqueous ammonium bicarbonate (10 mmol) adjusted to pH 10 with ammonia and acetonitrile was used as the mobile phase to give the title compound, which was converted to the hydrochloride salt and crystallized as an isomeric mixture from diethyl ether (42 mg). .
1HNMR (hydrochloride) δ (d ⁶ DMSO): 1.5-2.2 (9H, m), 2.35 (3H, s), 2.8 (2H, m), 3.2-3.6 (11H, m), 4.4 (0.4H, m ), 4.55 (1H, m), 4.7 (0.6H, br s), 6.8-6.9 (2H, m), 7.5 (1H, 2s), 10.55 (0.6H, br s), 10.7 (0.4H, br s) ), 10.8 (1H, 2s), MH + 398

（Ｅ２２）
０℃にてアルゴン下、ジクロロメタン（２０ｍｌ）中、Ｎ^２−（１−｛シス−４−［（シクロプロピルメチル）オキシ］シクロヘキシル｝−４−ピペリジニル）−４−メチル−１，２−ベンゼンジアミン（Ｄ９１、６００ｍｇ）およびジイソプロピルエチルアミン（０．６ｍｌ）の攪拌溶液を固体トリホスゲン（０．２ｇ、０．６７ｍｍｏｌ）で一度に処理し、室温で一晩攪拌した。この混合物をジクロロメタンで希釈し、希ＮａＨＣＯ_３溶液、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、溶媒を除去し、残渣をジクロロメタン−メタノール性アンモニア０〜１０％で溶出するシリカゲルでのクロマトグラフィーに付した。生成物をメタノールに溶解し、１Ｍ ＨＣｌ／ジエチルエーテルで処理し、真空濃縮し、標題化合物の塩酸塩を白色固体として得た（３８ｍｇ）。ＭＨ^＋＝３８４
¹H NMR δ(DMSO, 400 MHz): 0.2 (2H, m), 0.5 (2H, m), 1.05 (1H, m), 1.4 (2H , m), 1.7 (2H, m), 1.9 (4H, m), 2.0 (2H, m), 2.33 (3H, s), 2.75 (2H, m), 3.3 (obs, m), 3.55 (3H, m), 4.55, (1H, m), 6.79 (1H, d), 6.88 (1H, d) 7.33 (1H, s), 9.75 (1H, m), 10.8 (1H, s) Example 22.1- (1- {cis-4-[(cyclopropylmethyl) oxy] cyclohexyl} -4-piperidinyl) -6-methyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E22)

(E22)
Under argon at 0 ° C., in dichloromethane ^{(20ml), N 2 - (} 1- { cis-4 - [(cyclopropylmethyl) oxy] cyclohexyl} -4-piperidinyl) -4-methyl-1,2-benzenediamine A stirred solution of (D91, 600 mg) and diisopropylethylamine (0.6 ml) was treated with solid triphosgene (0.2 g, 0.67 mmol) in one portion and stirred overnight at room temperature. The mixture is diluted with dichloromethane, washed with dilute NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ , the solvent is removed and the residue is chromatographed on silica gel eluting with dichloromethane-methanolic ammonia 0-10%. It was attached to. The product was dissolved in methanol, treated with 1M HCl / diethyl ether and concentrated in vacuo to give the hydrochloride salt of the title compound as a white solid (38 mg). MH ⁺ = 384
¹ H NMR δ (DMSO, 400 MHz): 0.2 (2H, m), 0.5 (2H, m), 1.05 (1H, m), 1.4 (2H, m), 1.7 (2H, m), 1.9 (4H, m), 2.0 (2H, m), 2.33 (3H, s), 2.75 (2H, m), 3.3 (obs, m), 3.55 (3H, m), 4.55, (1H, m), 6.79 (1H, d), 6.88 (1H, d) 7.33 (1H, s), 9.75 (1H, m), 10.8 (1H, s)

（Ｅ２３）
０℃にてアルゴン下、ジクロロメタン（２０ｍｌ）中、Ｎ^２−（１−｛トランス−４−［（シクロプロピルメチル）オキシ］シクロヘキシル｝−４−ピペリジニル）−４−メチル−１，２−ベンゼンジアミン（Ｄ９２、３８０ｍｇ、１．０６ｍｍｏｌ）およびジイソプロピルエチルアミン（０．３ｍｌ）の攪拌溶液を固体トリホスゲン（１２６ｍｇ、０．４２ｍｍｏｌ）で処理し、室温で一晩攪拌した。この混合物をジクロロメタンで希釈し、希ＮａＨＣＯ_３溶液、ブラインで洗浄し、でＮａ_２ＳＯ_４乾燥させ、溶媒を除去した。標題化合物をエタノールから白色固体として得た（２７０ｍｇ）。この材料をメタノール／ジクロロメタンに溶解し、１Ｍ ＨＣｌ／ジエチルエーテルで処理し、真空濃縮し、標題化合物の塩酸塩を白色固体として得た（２７０ｍｇ）。ＭＨ^＋＝３８４
¹H NMR δ(DMSO, 400 MHz): 0.15 (2H, m), 0.45 (2H, m), 0.95 (1H, m), 1.2 (2H , m), 1.55 (2H, m), 1.85 (2H, m), 2.1 (4H, m), 2.32 (3H, s), 2.85 (2H, m), 2.9 (2H, m), 3.22 (obs, m), 3.5 (2H, m), 4.55, (1H, m), 6.80 (1H, d), 6.87 (1H, d) 7.51 (1H, s), 10.6 (1H, m), 10.8 (1H, s) Example 23.1- (1- {trans-4-[(cyclopropylmethyl) oxy] cyclohexyl} -4-piperidinyl) -6-methyl-1,3-dihydro-2H-benzimidazol-2-one (E23 )

(E23)
Under argon at 0 ° C., in dichloromethane ^{(20ml), N 2 - (} 1- { trans-4 - [(cyclopropylmethyl) oxy] cyclohexyl} -4-piperidinyl) -4-methyl-1,2-benzenediamine A stirred solution of (D92, 380 mg, 1.06 mmol) and diisopropylethylamine (0.3 ml) was treated with solid triphosgene (126 mg, 0.42 mmol) and stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with dilute NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ and the solvent removed. The title compound was obtained as a white solid from ethanol (270 mg). This material was dissolved in methanol / dichloromethane, treated with 1M HCl / diethyl ether and concentrated in vacuo to give the hydrochloride salt of the title compound as a white solid (270 mg). MH ⁺ = 384
¹ H NMR δ (DMSO, 400 MHz): 0.15 (2H, m), 0.45 (2H, m), 0.95 (1H, m), 1.2 (2H, m), 1.55 (2H, m), 1.85 (2H, m), 2.1 (4H, m), 2.32 (3H, s), 2.85 (2H, m), 2.9 (2H, m), 3.22 (obs, m), 3.5 (2H, m), 4.55, (1H, m), 6.80 (1H, d), 6.87 (1H, d) 7.51 (1H, s), 10.6 (1H, m), 10.8 (1H, s)

（Ｅ２４）
０℃にて、ジクロロメタン（３ｍｌ）中、トランス−５−メチル−Ｎ−［１−（４−シクロブチルオキシシクロヘキシル）−４−ピペリジニル］−１，２−ベンゼンジアミン（Ｄ９８、５０ｍｇ、０．１４ｍｍｏｌ）の溶液を、トリホスゲン（２０ｍｇ、０．４当量）、次いでジイソプロピルエチルアミン（０．０４ｍｌ、１．５当量）で処理した後、０℃で１時間維持した。この混合物をジクロロメタンで分液し、重炭酸ナトリウム水溶液で洗浄した。乾燥させ、蒸発させ、結晶化させ、単離した標題化合物をジエチルエーテルから塩酸塩として結晶化させた（３１ｍｇ）。
1HNMR (塩酸塩)δ(d⁶DMSO): 1.2 (2H, m), 1.5 (4H, m), 1.9 (3H, m), 2.15 (5H, m), 2.35 (3H, s), 2.8 (2H, m), 3.2 (4H, m), 3.5 (2H, m), 4.0 (1H, m), 4.6 (1H, m), 6.8 (2H, m), 7.4 (1H, s), 10.2 (1H, br s), 10.8 (1H, s), MH+ 384 Example 24. Trans-6-methyl-1- [1- (4-cyclopropyloxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E24)

(E24)
Trans-5-methyl-N- [1- (4-cyclobutyloxycyclohexyl) -4-piperidinyl] -1,2-benzenediamine (D98, 50 mg, 0.14 mmol in dichloromethane (3 ml) at 0 ° C. ) Was treated with triphosgene (20 mg, 0.4 eq) followed by diisopropylethylamine (0.04 ml, 1.5 eq) and then maintained at 0 ° C. for 1 h. The mixture was partitioned with dichloromethane and washed with aqueous sodium bicarbonate. Drying, evaporation, crystallization and the isolated title compound was crystallized as the hydrochloride salt from diethyl ether (31 mg).
1HNMR (hydrochloride) δ (d ⁶ DMSO): 1.2 (2H, m), 1.5 (4H, m), 1.9 (3H, m), 2.15 (5H, m), 2.35 (3H, s), 2.8 (2H , m), 3.2 (4H, m), 3.5 (2H, m), 4.0 (1H, m), 4.6 (1H, m), 6.8 (2H, m), 7.4 (1H, s), 10.2 (1H, br s), 10.8 (1H, s), MH + 384

Examples 25 and 26. Cis and trans-1- (1- [4- (propyloxy) cyclohexyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (cis = E25; trans = E26)

マイクロ波容器に４−（２−オキソ−１−ベンズイミダゾリニル）ピペリジン（０．２１７ｇ、１ｍｍｏｌ）、４−プロポキシシクロヘキサノン（Ｄ１９、０．２２ｇ、１．４１ｍｍｏｌ）、酢酸（０．２ｍｌ）、ジクロロメタン（１５ｍｌ）およびシアノ水素化ホウ素（ポリスチリルメチル）トリメチルアンモニウム（４．３ミリ当量／ｇ）（０．７５ｇ）を入れ、マイクロ波反応装置にて１１０℃で２０分間加熱した。さらなる４−プロポキシシクロヘキサノン（０．１５６ｇ、１．０ｍｍｏｌ）およびシアノ水素化ホウ素（ポリスチリルメチル）トリメチルアンモニウム（３００ｍｇ）を加え、この混合物をマイクロ波反応装置にて１１０℃でさらに２０分間加熱した。冷却混合物を真空下で濾過し、濾液を５ｇ ＳＣＸカートリッジに乗せ、メタノール、次いでメタノール性アンモニアで溶出した。メタノール性アンモニア画分から溶媒を除去して３００ｍｇの透明結晶を得、これを、Ｗａｔｅｒｓ Ｘｂｒｉｄｇｅクロマトグラフィーカラムおよび移動相として重炭酸アンモニウム水溶液（１０ｍｍｏｌ；アンモニアでｐＨ１０に調整）とアセトニトリルの勾配を用いて精製し、シスおよびトランス異性体を得た。得られたとことで、各異性体をジクロロメタン（２ｍｌ）に溶解し、ジエチルエーテル中１ｍｏｌのＨＣｌ（０．５ｍｌ）を加えた後、溶媒を除去し、標題化合物を得た。

In a microwave vessel, 4- (2-oxo-1-benzimidazolinyl) piperidine (0.217 g, 1 mmol), 4-propoxycyclohexanone (D19, 0.22 g, 1.41 mmol), acetic acid (0.2 ml), Dichloromethane (15 ml) and cyanoborohydride (polystyrylmethyl) trimethylammonium (4.3 meq / g) (0.75 g) were added and heated in a microwave reactor at 110 ° C. for 20 minutes. Additional 4-propoxycyclohexanone (0.156 g, 1.0 mmol) and cyanoborohydride (polystyrylmethyl) trimethylammonium (300 mg) were added and the mixture was heated in a microwave reactor at 110 ° C. for an additional 20 minutes. The cooled mixture was filtered under vacuum and the filtrate was loaded onto a 5 g SCX cartridge and eluted with methanol followed by methanolic ammonia. Removal of the solvent from the methanolic ammonia fraction yielded 300 mg of clear crystals that were purified using a Waters Xbridge chromatography column and a gradient of aqueous ammonium bicarbonate (10 mmol; adjusted to pH 10 with ammonia) and acetonitrile as the mobile phase. The cis and trans isomers were obtained. As a result, each isomer was dissolved in dichloromethane (2 ml), 1 mol HCl in diethyl ether (0.5 ml) was added, and then the solvent was removed to give the title compound.

The fast eluting isomer (trans isomer; E26) was obtained as a white solid (44 mg). MH ⁺ = 358
¹ HNMR δd ⁶ DMSO, 250 MHz): 0.86 (3H, t), 1.1-1.3 (3H, m), 1.4-1.7 (4H, m), 1.8-2.0 (2H, m), 2.0-2.2 (4H, d ), 2.7-2.9 (2H, m), 3.1-3.5 (assuming 5H, m), 3.5-3.6 (2H, m), 4.5-4.7 (1H, m), 7.0 (3H, m), 7.4-7.6 (1H, m), 10.0 (1H, s), 10.9 (1H, s)

Slowly eluting isomer (cis isomer; E25) was obtained as a white solid (15 mg). MH ⁺ = 358
¹ HNMR δd ⁶ DMSO, 250 MHz): 0.9 (3H, t), 1.35-2.1 (assuming 13H, br m), 2.6-2.9 (2H, br s), 3.1-3.45 (assuming 5H, br m), 3.5 (2H, br s), 4.45-4.7 (1H, br m), 7.0 (3H, s), 7.5 (1H, br m), 10.0 (1H, br s), 10.9 (1H, s)

（Ｅ２７）
０℃にて、ジクロロメタン（５０ｍｌ）中、４−ブロモ−Ｎ^２−｛１−［トランス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジニル｝−１，２−ベンゼンジアミン（Ｄ１００、５７４ｍｇ、１．４ｍｍｏｌ）およびジイソプロピルエチルアミン（０．３５ｍｌ、２．１ｍｍｏｌ）の攪拌溶液をトリホスゲン（１６６ｍｇ、０．５６ｍｍｏｌ）で処理し、０℃で３０分間攪拌した。この混合物を水および飽和ＮａＨＣＯ_３溶液で洗浄した後、ジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮して白色固体を得、これを１０％Ｅｔ_２Ｏ／石油エーテルの混合物で洗浄し、標題化合物の遊離塩基を得た（３９８ｍｇ、６５％）。この一部（１９８ｍｇ）をジクロロメタン（１０ｍｌ）に溶解し、１Ｍ ＨＣｌ／Ｅｔ_２Ｏ（５ｍｌ）で処理し、３０分間攪拌した後、真空濃縮し、標題化合物を白色固体として得た（２００ｍｇ）。ＭＨ＋＝４３７、４３８
¹H NMR δ(d⁶DMSO, 400MHz): 0.87 (3H, t), 1.12-1.30 (2H, m), 1.42-1.63 (4H, m), 1.90 (2H, br d), 2.05-2.20 (4H, m), 2.70-2.85 (2H, m), 3.10-3.30 (4H, m), 4.43-4.54 (2H, m), 4.50-4.65 (1H, m), 6.95 (1H, d), 7.16 (1H, dd), 7.68 (1H, s), 10.32 (1H, br m), 11.12 (1H, s) Example 27 6-Bromo-1- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E27)

(E27)
At 0 ° C., in dichloromethane (50 ml), 4-bromo ^-N 2 - {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D100,574mg, 1 .4 mmol) and diisopropylethylamine (0.35 ml, 2.1 mmol) were treated with triphosgene (166 mg, 0.56 mmol) and stirred at 0 ° C. for 30 min. The mixture was washed with water and saturated NaHCO ₃ solution and then extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a white solid which was washed with a mixture of 10% Et ₂ O / petroleum ether to give the free base of the title compound (398 mg, 65% ). A portion (198 mg) was dissolved in dichloromethane (10 ml), treated with 1M HCl / Et ₂ O (5 ml), stirred for 30 minutes and then concentrated in vacuo to give the title compound as a white solid (200 mg). MH + = 437, 438
¹ H NMR δ (d ⁶ DMSO, 400MHz): 0.87 (3H, t), 1.12-1.30 (2H, m), 1.42-1.63 (4H, m), 1.90 (2H, br d), 2.05-2.20 (4H , m), 2.70-2.85 (2H, m), 3.10-3.30 (4H, m), 4.43-4.54 (2H, m), 4.50-4.65 (1H, m), 6.95 (1H, d), 7.16 (1H , dd), 7.68 (1H, s), 10.32 (1H, br m), 11.12 (1H, s)

（Ｅ２８）
０℃にて、ジクロロメタン（１５ｍｌ）中、４−エチル−Ｎ^２−｛１−［トランス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジニル｝−１，２−ベンゼンジアミン（Ｄ１０２、１８０ｍｇ、０．５ｍｍｏｌ）およびジイソプロピルエチルアミン（０．０８５ｍｌ、０．７５ｍｍｏｌ）の攪拌溶液をトリホスゲン（５９．２ｍｇ、０．１２ｍｍｏｌ）で処理し、０℃で３０分間攪拌した。この混合物を水および飽和ＮａＨＣＯ_３溶液で洗浄した後、ジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、白色固体を得た。これをジクロロメタン（５ｍｌ）に溶解し、ＨＣｌ／Ｅｔ_２Ｏ（３ｍｌ）で処理し、真空濃縮し、標題化合物を白色固体として得た（２００ｍｇ、９５％）。ＭＨ＋＝３８６
¹H NMR δ(d⁶DMSO, 400MHz): 0.86 (3H, t), 1.15-1.30 (5H, t + m), 1.42-1.62 (4H, m), 1.82-1.92 (2H, m), 2.08-2.18 (4H, m), 2.61 (2H, q), 2.76-2.90 (2H, m), 3.14-3.3 (4H, m), 3.38 (2H, t), 3.50 (2H, br d), 4.50-4.62 (1H, m), 6.83 (1H, d), 6.89 (1H, d), 7.43 (1H, s), 10.35 (1H, br m), 10.78 (1H, s) Example 28 6-Ethyl-1- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E28)

(E28)
At 0 ° C., in dichloromethane (15 ml), 4-ethyl ^-N 2 - {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D102,180mg, 0 .5 mmol) and diisopropylethylamine (0.085 ml, 0.75 mmol) were treated with triphosgene (59.2 mg, 0.12 mmol) and stirred at 0 ° C. for 30 minutes. The mixture was washed with water and saturated NaHCO ₃ solution and then extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a white solid. This was dissolved in dichloromethane (5 ml), treated with HCl / Et ₂ O (3 ml) and concentrated in vacuo to give the title compound as a white solid (200 mg, 95%). MH + = 386
¹ H NMR δ (d ⁶ DMSO, 400MHz): 0.86 (3H, t), 1.15-1.30 (5H, t + m), 1.42-1.62 (4H, m), 1.82-1.92 (2H, m), 2.08- 2.18 (4H, m), 2.61 (2H, q), 2.76-2.90 (2H, m), 3.14-3.3 (4H, m), 3.38 (2H, t), 3.50 (2H, br d), 4.50-4.62 (1H, m), 6.83 (1H, d), 6.89 (1H, d), 7.43 (1H, s), 10.35 (1H, br m), 10.78 (1H, s)

（Ｅ２９）
０℃にて、ジクロロメタン（１０ｍｌ）中、４−シクロプロピル−Ｎ^２−｛１−［トランス−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジニル｝−１，２−ベンゼンジアミン（Ｄ１０４、７０ｍｇ、０．２ｍｍｏｌ）およびジイソプロピルエチルアミン（０．５ｍｌ）の攪拌溶液をトリホスゲン（２８ｍｇ、０．１ｍｍｏｌ）で処理し、０℃にて３０分間攪拌した。この溶液を水および飽和ＮａＨＣＯ_３溶液で洗浄した後、ジクロロメタンで抽出した。抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残渣をジクロロメタン（５ｍｌ）に溶解し、１Ｍ ＨＣｌ／Ｅｔ_２Ｏ（１ｍｌ）で処理し、３０分間攪拌し、真空濃縮し、標題化合物を得た（７０ｍｇ、８１％）。ＭＨ＋＝３９８
¹H NMR δ(d⁶DMSO, 400MHz): 0.70 0.78 (2H, m), 0.83-0.91 (5H, t + m), 1.12-1.28 (2H, m), 1.42-1.62 (4H, m), 1.82 (2H, br d), 1.90-2.00 (1H, m), 2.10 (2H, br d), 2.18 (2H, br d), 2.85-3.00 (2H, m), 3.12-3.30 (4H, m), 3.37 (2H, t), 3.48 (2H, br d), 4.52-4.62 (1H, m), 6.70 (1H, dd), 6.85 (1H, d), 7.38 (1H, s), 10.78 (1H, s), 11.04 (1H, br m) Example 29 6-Cyclopropyl-1- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E29)

(E29)
4-Cyclopropyl-N ^2- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D104, 70 mg, in dichloromethane (10 ml) at 0 ° C. A stirred solution of 0.2 mmol) and diisopropylethylamine (0.5 ml) was treated with triphosgene (28 mg, 0.1 mmol) and stirred at 0 ° C. for 30 min. The solution was washed with water and saturated NaHCO ₃ solution and then extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dissolved in dichloromethane (5 ml), treated with 1M HCl / Et ₂ O (1 ml), stirred for 30 minutes and concentrated in vacuo to give the title compound (70 mg, 81%). MH + = 398
¹ H NMR δ (d ⁶ DMSO, 400MHz): 0.70 0.78 (2H, m), 0.83-0.91 (5H, t + m), 1.12-1.28 (2H, m), 1.42-1.62 (4H, m), 1.82 (2H, br d), 1.90-2.00 (1H, m), 2.10 (2H, br d), 2.18 (2H, br d), 2.85-3.00 (2H, m), 3.12-3.30 (4H, m), 3.37 (2H, t), 3.48 (2H, br d), 4.52-4.62 (1H, m), 6.70 (1H, dd), 6.85 (1H, d), 7.38 (1H, s), 10.78 (1H, s ), 11.04 (1H, br m)

マイクロ波容器に１−（４−ピペリジニル）−６−［（トリフルオロメチル）オキシ］−１，３−ジヒドロ−２Ｈ−ベンズイミダゾール−２−オン（Ｄ８３、３３７ｍｇ）、４−（プロピルオキシ）シクロヘキサノン（Ｄ１９、１９０ｍｇ）シアノ水素化ホウ素（ポリスチリルメチル）トリメチルアンモニウム（４．３ミリ当量／ｇ ０．６ｇ）、酢酸ナトリウム（１００ｍｇ）、ジクロロメタン（１０ｍｌ）、酢酸（２００μｌ）を入れ、マイクロ波反応装置にて１１０℃で計３０分間加熱した。冷却混合物を濾過し、濾液をＳＣＸカートリッジに乗せ、メタノール、次いでメタノール性アンモニアで溶出した。メタノール性アンモニア画分を蒸発させ、得られた混合物を、Ｗａｔｅｒｓ Ｘｂｒｉｄｇｅクロマトグラフィーカラムを用いて精製した。重炭酸アンモニウム水溶液（１０ｍｍｏｌ アンモニアでｐＨ１０に調整）とアセトニトリルを用いた勾配を移動相として用い、シスおよびトランス異性体を得た。 Examples 30 and 31. Cis and trans-1- {1- [4- (propyloxy) cyclohexyl] -4-piperidinyl} -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one ( Cis = E30; trans = E31)

1- (4-Piperidinyl) -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one (D83, 337 mg), 4- (propyloxy) cyclohexanone in a microwave container (D19, 190 mg) Cyanoborohydride (polystyrylmethyl) trimethylammonium (4.3 meq / g 0.6 g), sodium acetate (100 mg), dichloromethane (10 ml), acetic acid (200 μl) were added, and microwave reaction The apparatus was heated at 110 ° C. for a total of 30 minutes. The cooled mixture was filtered and the filtrate was loaded onto an SCX cartridge and eluted with methanol followed by methanolic ammonia. The methanolic ammonia fraction was evaporated and the resulting mixture was purified using a Waters Xbridge chromatography column. A cis and trans isomer was obtained using a gradient with aqueous ammonium bicarbonate (pH adjusted to 10 with 10 mmol ammonia) and acetonitrile as the mobile phase.

An early eluting isomer (trans isomer; E31) was obtained as a white solid (0.071 g). MH ⁺ = 442
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.91 (3H, t), 1.2-1.4 (5H, m), 1.85 (2H, m), 1.94 (2H, m), 2.11 (2H, m), 2.4 (4H, m), 3.07 (2H, m), 3.15 (1H, m), 3.41 (2H, t), 4.30 (1H, m), 6.93 (1H, d), 7.02 (1H, d) 7.16 (1H , m), 9.02 (1H, s)
¹⁹ F NMR δ (d ⁶ DMSO) -58.24 ppm

Slowly eluting isomer (cis isomer: E30) was obtained as a white solid (0.077 g). MH ⁺ = 442
¹ H NMR δ (CDCl ₃ , 400 MHz): 0.91 (3H, t), 1.4 (2H, m), 1.55-1.75 (6H, m), 1.82 (2H, m), 2.00 (2H, m), 2.3 -2.5 (4H, m), 3.07 (2H, m), 3.15 (1H, m), 3.33 (2H, t), 3.45 (1H, m), 4.30 (1H, m), 6.93 (1H, d) 7.04 (1H, d), 7.17 (1H, m), 9.16 (1H, s)
¹⁹ F NMR δ (d ⁶ DMSO) -58.23 ppm

（Ｅ３２）
０℃にてアルゴン下、ジクロロメタン（１０ｍｌ）中、Ｎ^２−｛１−［シス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジニル｝−４−メチル−１，２−ベンゼンジアミン（Ｄ１０６、１５０ｍｇ、０．４４ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（０．１１６ｍｌ、０．６５ｍｍｏｌ）で処理した後、固体トリホスゲン（５１ｍｇ、０．１７４ｍｍｏｌ）を加え、０℃で１．５時間維持した。この混合物を希ＮａＨＣＯ_３溶液（１０ｍｌ）で処理し、ジクロロメタンで抽出した（２×１０ｍｌ）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、固体残渣をジクロロメタン／ＥｔＯＡｃから再結晶させ、標題化合物の遊離塩基を白色固体として得た（１１５ｍｇ、７１％）。この一部の材料（８４ｍｇ）をジクロロメタン（２ｍｌ）とＭｅＯＨ（５ｍｌ）の混合物に溶解し、１Ｍ ＨＣｌ／Ｅｔ_２Ｏ（０．３５ｍｌ）で処理し、真空濃縮した。Ｅｔ_２Ｏでトリチュレートして固体を得、これを濾別し、Ｅｔ_２Ｏで洗浄し、乾燥させ、標題化合物を白色固体として得た（８６ｍｇ）。ＭＨ^＋＝３７２
¹H NMR δ(d⁶DMSO, 400MHz): 1.13 (3H, t), 1.36 (3H, s), 1.48-1.62 (2H, m), 1.67-1.77 (2H, m), 1.80-1.92 (4H, br m), 1.92-2.05 (2H, m), 2.33 (3H, s), 2.82-3.00 (2H, m), 3.13-3.27 (2H, m), 3.41 (2H, q), 3.50 (1H, s), 3.67 (2H, br d), 4.55-4.67 (1H, m), 6.79 (1H, d), 6.87 (1H, d), 7.55 (1H, s), 9.95 (1H, br m), 10.80 (1H, s) Example 32.1- {1- [cis-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -6-methyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride ( E32)

(E32)
N ^2- {1- [cis-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -4-methyl-1,2-benzenediamine (10 ml) in dichloromethane (10 ml) at 0 ° C. A stirred solution of D106, 150 mg, 0.44 mmol) was treated with diisopropylethylamine (0.116 ml, 0.65 mmol), then solid triphosgene (51 mg, 0.174 mmol) was added and maintained at 0 ° C. for 1.5 hours. The mixture was treated with dilute NaHCO ₃ solution (10 ml) and extracted with dichloromethane (2 × 10 ml). The combined extracts were dried (Na ₂ SO ₄ ), concentrated in vacuo and the solid residue was recrystallized from dichloromethane / EtOAc to give the free base of the title compound as a white solid (115 mg, 71%). This portion of material (84 mg) was dissolved in a mixture of dichloromethane (2 ml) and MeOH (5 ml), treated with 1M HCl / Et ₂ O (0.35 ml) and concentrated in vacuo. Trituration with Et ₂ O gave a solid which was filtered off, washed with Et ₂ O and dried to give the title compound as a white solid (86 mg). MH ⁺ = 372
¹ H NMR δ (d ⁶ DMSO, 400 MHz): 1.13 (3H, t), 1.36 (3H, s), 1.48-1.62 (2H, m), 1.67-1.77 (2H, m), 1.80-1.92 (4H, br m), 1.92-2.05 (2H, m), 2.33 (3H, s), 2.82-3.00 (2H, m), 3.13-3.27 (2H, m), 3.41 (2H, q), 3.50 (1H, s ), 3.67 (2H, br d), 4.55-4.67 (1H, m), 6.79 (1H, d), 6.87 (1H, d), 7.55 (1H, s), 9.95 (1H, br m), 10.80 ( 1H, s)

（Ｅ３３）
０℃にてアルゴン下、ジクロロメタン（１０ｍｌ）中、Ｎ^２−｛１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジニル｝−４−メチル−１，２−ベンゼンジアミン（Ｄ１０８、１６０ｍｇ、０．４６４ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（０．１２４ｍｌ、０．６９６ｍｍｏｌ）で処理した後、固体トリホスゲン（５５ｍｇ、０．１８６ｍｍｏｌ）を加え、０℃で１．５時間維持した。この混合物を希ＮａＨＣＯ_３溶液（１０ｍｌ）で処理し、ジクロロメタンで抽出した（２×１０ｍｌ）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、残渣を１：１ Ｅｔ_２Ｏ／ＥｔＯＡｃから結晶化させ、標題化合物の遊離塩基を白色固体として得た（１２０ｍｇ、７０％）。この一部の材料（８５ｍｇ）をジクロロメタン（３ｍｌ）とＭｅＯＨ（５ｍｌ）の混合物に溶解し、１Ｍ ＨＣｌ／Ｅｔ_２Ｏ（０．３５ｍｌ）で処理し、真空濃縮した。残渣をＥｔ_２Ｏでトリチュレートして固体を得、これを濾別し、Ｅｔ_２Ｏで洗浄し、乾燥させ、標題化合物を白色固体として得た（８６ｍｇ）。ＭＨ^＋＝３７２
¹H NMR δ(d⁶DMSO, 400MHz): 1.11 (3H, t), 1.22-1.40 (2H, m), 1.34 (3H, s), 1.85 (2H, br d), 1.90-2.05 (6H, m), 2.32 (3H, s), 2.86-3.01 (2H, m), 3.12-3.38 (3H, m), 3.47 (2H, q), 3.65 (2H, br d), 4.54-4.68 (1H, m), 6.79 (1H, d), 6.86 (1H, d), 7.65 (1H, s), 10.40 (1H, br m), 10.76 (1H, s) Example 33.1- {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -6-methyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride ( E33)

(E33)
N ^2- {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -4-methyl-1,2-benzenediamine (10 ml) in dichloromethane (10 ml) at 0 ° C. under argon. After treating a stirred solution of D108, 160 mg, 0.464 mmol) with diisopropylethylamine (0.124 ml, 0.696 mmol), solid triphosgene (55 mg, 0.186 mmol) was added and maintained at 0 ° C. for 1.5 hours. The mixture was treated with dilute NaHCO ₃ solution (10 ml) and extracted with dichloromethane (2 × 10 ml). The combined extracts were dried (Na ₂ SO ₄ ), concentrated in vacuo, and the residue was crystallized from 1: 1 Et ₂ O / EtOAc to give the free base of the title compound as a white solid (120 mg, 70%) . This portion of material (85 mg) was dissolved in a mixture of dichloromethane (3 ml) and MeOH (5 ml), treated with 1M HCl / Et ₂ O (0.35 ml) and concentrated in vacuo. The residue was triturated with Et ₂ O to give a solid which was filtered off, washed with Et ₂ O and dried to give the title compound as a white solid (86 mg). MH ⁺ = 372
¹ H NMR δ (d ⁶ DMSO, 400MHz): 1.11 (3H, t), 1.22-1.40 (2H, m), 1.34 (3H, s), 1.85 (2H, br d), 1.90-2.05 (6H, m ), 2.32 (3H, s), 2.86-3.01 (2H, m), 3.12-3.38 (3H, m), 3.47 (2H, q), 3.65 (2H, br d), 4.54-4.68 (1H, m) , 6.79 (1H, d), 6.86 (1H, d), 7.65 (1H, s), 10.40 (1H, br m), 10.76 (1H, s)

（Ｅ３４）
（２−アミノ−５−メチルフェニル）｛１−［シス−１−メチル−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジニル｝アミン（Ｄ１１２、５３ｍｇ、０．１２８ｍｍｏｌ）をジクロロメタン（５ｍｌ）に溶解し、Ｈｕｎｉｇｈ塩基ジイソプロピルエチルアミン（１．５当量、３２μｌ）を加えた。次に、この混合物を０℃まで冷却した後、ビス（トリクロロメチル）カーボネート（０．４当量、０．０５ｍｍｏｌ、１５ｍｇ）を０℃にて少量ずつ加えた。この混合物を同じ温度で１．５時間攪拌した後、ブラインでクエンチし、ｐＨ＝１０の塩基性とし、得られた水溶液をＥｔＯＡｃで抽出した（２回）。有機液を合わせ、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、溶媒を蒸発させて粗生成物を得、これをシリカクロマトグラフィー（ＭｅＯＨ−ＮＨ_３−ジクロロメタン）により精製し、標題化合物の遊離塩基を得た（４０ｍｇ、７５％）。次に、これをジクロロメタン（２ｍｌ）に溶解し、室温にてＨＣｌ溶液（Ｅｔ_２Ｏ中１Ｍ、０．２ｍｌ）で処理した。この混合物を室温で一晩攪拌した後、溶媒を蒸発させ、標題化合物を得た（４３ｍｇ、完全に変換）。Ｍ^＋＋Ｈ＝３８５
¹HNMR δ(DMSO, 500 MHz): 0.900 (3H, t), 1.351 (3H, s), 1.524 (4H, m), 1.728 (2H, d), 1.909 (6H, m), 2.341 (3H, s), 2.809 (2H, q), 3.177 (2H, q), 3.329 (2H, t), 3.467 (1H, s br), 3.667 (2H, d), 3.567 (1H, m), 6.805 (1H, m), 6.872 (1H, d), 7.361 (1H, s), 9.461 (1H, t ブロード), 10.774 (1H, s) Example 34. 6-Methyl-1- {1- [cis-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one monohydrochloride Salt (E34)

(E34)
(2-Amino-5-methylphenyl) {1- [cis-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinyl} amine (D112, 53 mg, 0.128 mmol) dissolved in dichloromethane (5 ml) Hunigh base diisopropylethylamine (1.5 eq, 32 μl) was added. The mixture was then cooled to 0 ° C. and bis (trichloromethyl) carbonate (0.4 eq, 0.05 mmol, 15 mg) was added in portions at 0 ° C. The mixture was stirred at the same temperature for 1.5 hours, then quenched with brine, basified to pH = 10, and the resulting aqueous solution was extracted with EtOAc (2 times). The organics were combined, dried (Na ₂ SO ₄ ), filtered and the solvent evaporated to give the crude product, which was purified by silica chromatography (MeOH—NH ₃ -dichloromethane) to give the free base of the title compound (40 mg, 75%) was obtained. This was then dissolved in dichloromethane (2 ml) and treated with HCl solution (1M in Et ₂ O, 0.2 ml) at room temperature. After the mixture was stirred at room temperature overnight, the solvent was evaporated to give the title compound (43 mg, fully converted). M ⁺ + H = 385
¹ HNMR δ (DMSO, 500 MHz): 0.900 (3H, t), 1.351 (3H, s), 1.524 (4H, m), 1.728 (2H, d), 1.909 (6H, m), 2.341 (3H, s ), 2.809 (2H, q), 3.177 (2H, q), 3.329 (2H, t), 3.467 (1H, s br), 3.667 (2H, d), 3.567 (1H, m), 6.805 (1H, m ), 6.872 (1H, d), 7.361 (1H, s), 9.461 (1H, t broad), 10.774 (1H, s)

（Ｅ３５）
（２−アミノ−５−メチルフェニル）｛１−［トランス−１−メチル−４−（プロピルオキシ）シクロヘキシル］−４−ピペリジニル｝アミン（Ｄ１１３、４５ｍｇ、０．１２８ｍｍｏｌ）をジクロロメタン（５ｍｌ）に溶解し、Ｈｕｎｉｇｈ塩基（１．５当量、３２μｌ）を加えた。次に、この混合物を０℃まで冷却した後、ビス（トリクロロメチル）カーボネート（０．４当量、０．０５ｍｍｏｌ、１５ｍｇ）を０℃にて少量ずつ加えた。この混合物を同じ温度で１．５時間攪拌し、ブラインでクエンチし、ｐＨ＝１０の塩基性とし、得られた水溶液をＥｔＯＡｃで抽出した（２回）。有機液を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、溶媒を蒸発させて粗生成物を得、これをシリカクロマトグラフィー（ＭｅＯＨ−ＮＨ_３−ジクロロメタン）により精製し、標題化合物の遊離塩基を得た（５０ｍｇ、完全に変換）。次に、これをジクロロメタン（２ｍｌ）に溶解し、室温にてＨＣｌ溶液（Ｅｔ_２Ｏ中１Ｍ、０．２ｍｌ）で処理した。この混合物を室温で一晩攪拌した後、溶媒を蒸発させ、標題化合物を得た（５５ｍｇｓ、完全に変換）。Ｍ^＋＋Ｈ＝３８５
¹HNMR δ(DMSO, 500 MHz): 0.444 (3H, t), 1.287 (5H, m), 1.485 (2H, m), 1.919 (8H, m), 2.326 (3H, s), 2.903 (2H, q), 3.190 (3H, m), 3.376 (ウォーターピーク下2H), 3.640 (2H, d), 4.589 (1H, m), 6.793 (1H, d), 6.862 (1H, d), 7.578 (1H, s), 10.203 (1H, t ブロード), 10.760 (1H, s) Example 35. 6-Methyl-1- {1- [trans-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one monohydrochloride Salt (E35)

(E35)
(2-Amino-5-methylphenyl) {1- [trans-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinyl} amine (D113, 45 mg, 0.128 mmol) dissolved in dichloromethane (5 ml) Hunigh base (1.5 eq, 32 μl) was added. The mixture was then cooled to 0 ° C. and bis (trichloromethyl) carbonate (0.4 eq, 0.05 mmol, 15 mg) was added in portions at 0 ° C. The mixture was stirred at the same temperature for 1.5 hours, quenched with brine, basified to pH = 10, and the resulting aqueous solution was extracted with EtOAc (2 times). The organics were combined, dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated to give the crude product, which was purified by silica chromatography (MeOH—NH ₃ -dichloromethane) to give the free base of the title compound. Obtained (50 mg, fully converted). This was then dissolved in dichloromethane (2 ml) and treated with HCl solution (1M in Et ₂ O, 0.2 ml) at room temperature. After the mixture was stirred at room temperature overnight, the solvent was evaporated to give the title compound (55 mgs, complete conversion). M ⁺ + H = 385
¹ HNMR δ (DMSO, 500 MHz): 0.444 (3H, t), 1.287 (5H, m), 1.485 (2H, m), 1.919 (8H, m), 2.326 (3H, s), 2.903 (2H, q ), 3.190 (3H, m), 3.376 (2H under water peak), 3.640 (2H, d), 4.589 (1H, m), 6.793 (1H, d), 6.862 (1H, d), 7.578 (1H, s ), 10.203 (1H, t broad), 10.760 (1H, s)

（Ｅ３６）
０℃にて、ジクロロメタン（３ｍｌ）中、トランス５−メチル−Ｎ−［１−（１−エチル−４−プロポキシシクロヘキシル）−４−ピペリジニル］−１，２−ベンゼンジアミン（Ｄ１２６、４０ｍｇ、０．１ｍｍｏｌ）の溶液をトリホスゲン（１２ｍｇ、０．０４ｍｍｏｌ）、次いでジイソプロピルエチルアミン（０．０３ｍｌ、０．１５ｍｍｏｌ）で処理した後、０℃で３０分間維持した。この混合物をジクロロメタンと重炭酸ナトリウム水溶液とで分液した。乾燥させ、蒸発させ、ジエチルエーテルから結晶化させ、標題化合物を遊離塩基として得た。これを塩酸塩へ変換し、またジエチルエーテルから単離した（２０ｍｇ）。
1HNMR (HCl塩) δ(d⁶DMSO): 0.85 (3H, t), 1.05 (3H, t), 1.3 (2H, m), 1.5 (2H, m), 1.9 (4H, m), 2.05 (4H, m), 2.35 (3H, s), 2.8 (2H, m), 3.2 (2H, m), 3.6 (2H, m), 4.6 (1H, m), 6.8 (2H, m), 7.35 (1H, s), 9.1 (1H, br s), 10.8 (1H, s), MH+ 400 Example 36. Trans 6-methyl-1- [1- (1-ethyl-4-propoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E36)

(E36)
At 0 ° C., trans 5-methyl-N- [1- (1-ethyl-4-propoxycyclohexyl) -4-piperidinyl] -1,2-benzenediamine (D126, 40 mg, 0.3 mg) in dichloromethane (3 ml). 1 mmol) was treated with triphosgene (12 mg, 0.04 mmol) and then diisopropylethylamine (0.03 ml, 0.15 mmol) and then kept at 0 ° C. for 30 minutes. The mixture was partitioned between dichloromethane and aqueous sodium bicarbonate. Drying, evaporation and crystallization from diethyl ether gave the title compound as the free base. This was converted to the hydrochloride salt and isolated from diethyl ether (20 mg).
1HNMR (HCl salt) δ (d ⁶ DMSO): 0.85 (3H, t), 1.05 (3H, t), 1.3 (2H, m), 1.5 (2H, m), 1.9 (4H, m), 2.05 (4H , m), 2.35 (3H, s), 2.8 (2H, m), 3.2 (2H, m), 3.6 (2H, m), 4.6 (1H, m), 6.8 (2H, m), 7.35 (1H, s), 9.1 (1H, br s), 10.8 (1H, s), MH + 400

（Ｅ３７）
０℃にてアルゴン下、ジクロロメタン（１０ｍｌ）中、４−アミノ−３−（｛１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝アミノ）ベンゾニトリル（Ｄ１２８、１２０ｍｇ、０．３５ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（０．０９２ｍｌ、０．５２ｍｍｏｌ）で処理した後、固体トリホスゲン（４０ｍｇ、０．１４ｍｍｏｌ）を加え、１時間維持した。この混合物を１０％Ｎａ_２ＣＯ_３溶液（１０ｍｌ）で処理し、ジクロロメタンで抽出した（２×１５ｍｌ）。合わせた抽出液を乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮し、残渣を、アセトニトリル／水／０．１％ギ酸で溶出するＷａｔｅｒｓ Ｘｂｒｉｄｇｅクロマトグラフィーカラムを用いて精製し、標題化合物の遊離塩基を白色固体として得た（５０ｍｇ、３９％）。この材料（８５ｍｇ）をジクロロメタン（５ｍｌ）に溶解し、１Ｍ ＨＣｌ／Ｅｔ_２Ｏ（０．２ｍｌ）で処理し、真空濃縮し、標題化合物を白色固体として得た（５４ｍｇ）。ＭＨ^＋＝３６９
¹H NMR δ(d⁶DMSO, 400MHz): 1.09 (3H, t), 1.10-1.30 (2H, m), 1.47-1.63 (2H, m), 1.92 (2H, br d), 2.05-2.18 (4H, m), 2.71-2.88 (2H, m), 3.18-3.40 (4H, mと仮定), 3.4-3.55 (4H, mと仮定), 4.57-4.70 (1H, m), 7.16 (1H, d), 7.48 (1H, d), 7.99 (1H, s), 10.26 (1H, br m), 11.55 (1H, s) Example 37. 3- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile hydrochloride (E37)

(E37)
4-amino-3-({1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} amino) benzonitrile (D128, 120 mg, 0.35 mmol) in dichloromethane (10 ml) under argon at 0 ° C. ) Was treated with diisopropylethylamine (0.092 ml, 0.52 mmol), then solid triphosgene (40 mg, 0.14 mmol) was added and maintained for 1 hour. The mixture was treated with 10% Na ₂ CO ₃ solution (10 ml) and extracted with dichloromethane (2 × 15 ml). The combined extracts were dried (Na ₂ SO ₄ ), concentrated in vacuo, and the residue was purified using a Waters Xbridge chromatography column eluting with acetonitrile / water / 0.1% formic acid to give the free base of the title compound. Obtained as a white solid (50 mg, 39%). This material (85 mg) was dissolved in dichloromethane (5 ml), treated with 1M HCl / Et ₂ O (0.2 ml) and concentrated in vacuo to give the title compound as a white solid (54 mg). MH ⁺ = 369
¹ H NMR δ (d ⁶ DMSO, 400MHz): 1.09 (3H, t), 1.10-1.30 (2H, m), 1.47-1.63 (2H, m), 1.92 (2H, br d), 2.05-2.18 (4H , m), 2.71-2.88 (2H, m), 3.18-3.40 (assuming 4H, m), 3.4-3.55 (assuming 4H, m), 4.57-4.70 (1H, m), 7.16 (1H, d) , 7.48 (1H, d), 7.99 (1H, s), 10.26 (1H, br m), 11.55 (1H, s)

（Ｅ３８）
０℃にてアルゴン下、ジクロロメタン（１０ｍｌ）中、４−アミノ−３−（｛１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジニル｝アミノ）ベンゾニトリル（Ｄ１３０、６０ｍｇ、０．１６８ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（４２μＬ、０．２５２ｍｍｏｌ、３２．５ｍｇ）、次いで固体トリホスゲン（１９ｍｇ、０．０６７ｍｍｏｌ）で処理し、０℃で１時間維持した。この混合物をＮａＨＣＯ_３水溶液（１０ｍｌ）で処理し、ジクロロメタンで抽出した（２×１５ｍｌ）。合わせた抽出液を乾燥させ（ＭｇＳＯ_４）、真空濃縮し、橙色残渣を得た。次に、残渣を、Ｗａｔｅｒｓ Ｘｂｒｉｄｇｅクロマトグラフィーカラムを高ｐＨで用いて精製し、標題化合物の遊離塩基を得（２４ｍｇ、３８％）、その後、これを１Ｍ ＨＣｌ／ジエチルエーテル（０．２５ｍｌ）で処理し、溶媒を蒸発により除去し、標題化合物（２４ｍｇ、３４％）を白色固体として得た。
¹H NMR (遊離塩基) δ(CDCl₃, 400 MHz): 0.96 (3H, s), 1.21 (3H, t), 1.43-1.71 (6H, m), 1.84-1.94 (4H, m), 2.23-2.30 (4H, m), 3.18 (2H, d) 3.5 (1H, m), 3.52 (2H, q), 4.29 (1H, m), 7.15 (1H, d), 7.4 (1H, d), 7.52 (1H, s), 9.81 (1H, s) Example 38.3- {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile hydrochloride (E38)

(E38)
4-amino-3-({1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} amino) benzonitrile (D130, 60 mg) in dichloromethane (10 ml) under argon at 0 ° C. , 0.168 mmol) was treated with diisopropylethylamine (42 μL, 0.252 mmol, 32.5 mg) followed by solid triphosgene (19 mg, 0.067 mmol) and maintained at 0 ° C. for 1 hour. The mixture was treated with aqueous NaHCO ₃ (10 ml) and extracted with dichloromethane (2 × 15 ml). The combined extracts were dried (MgSO ₄ ) and concentrated in vacuo to give an orange residue. The residue was then purified using a Waters Xbridge chromatography column at high pH to give the free base of the title compound (24 mg, 38%), which was then treated with 1M HCl / diethyl ether (0.25 ml). The solvent was removed by evaporation to give the title compound (24 mg, 34%) as a white solid.
¹ H NMR (free base) δ (CDCl ₃ , 400 MHz): 0.96 (3H, s), 1.21 (3H, t), 1.43-1.71 (6H, m), 1.84-1.94 (4H, m), 2.23- 2.30 (4H, m), 3.18 (2H, d) 3.5 (1H, m), 3.52 (2H, q), 4.29 (1H, m), 7.15 (1H, d), 7.4 (1H, d), 7.52 ( 1H, s), 9.81 (1H, s)

（Ｅ３９）
室温にてアルゴン下、ＤＭＳＯ（１ｍｌ）中、６−ブロモ−１−｛１−［トランス−４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝−１，３−ジヒドロ−２Ｈ−ベンズイミダゾール−２−オン（Ｅ１４の遊離塩基）（１３０ｍｇ、０．３１ｍｍｏｌ）の攪拌溶液をメタンスルフィン酸ナトリウム（３５ｍｇ、０．３４ｍｍｏｌ）、ヨウ化銅（Ｉ）（５．９ｍｇ、０．０３１ｍｍｏｌ）およびＬ−プロリンナトリウム塩（８．５ｍｇ、０．０６２ｍｍｏｌ）で処理した後、９５℃で１８時間加熱した。さらなるスルフィン酸ナトリウム（７０ｍｇ）、ヨウ化銅（Ｉ）（１２ｍｇ）およびＬ−プロリンナトリウム塩（１７ｍｇ）を加え、この混合物を９５℃でさらに５８時間加熱した。この混合物を冷却した後、１０％Ｎａ_２ＣＯ_３溶液（２０ｍｌ）およびＥｔＯＡｃ（２５ｍｌ）で処理し、よく振盪し、Ｋｉｅｓｅｌｇｕｈｒで濾過した。ＥｔＯＡｃ層を単離し、乾燥させ（Ｎａ_２ＳＯ_４）、真空濃縮した。残渣を、アセトニトリル／水／０．１％ギ酸で溶出するＷａｔｅｒｓ Ｘｂｒｉｄｇｅクロマトグラフィーカラムカラムを用いて精製し、標題化合物の遊離塩基を白色固体として得た（１２ｍｇ）。これを黄色固体としての標題化合物へ変換した。ＭＨ＋＝４２２
¹H NMR (遊離塩基) δ(CDCl₃, 400MHz): 1.20-1.40 (4H, m), 1.21 (3H, t), 1.80-2.05 (4H, m), 2.10-2.20 (2H, m), 2.34-2.52 (5H, mと仮定), 3.02-3.12 (2H, mと仮定), 3.10 (3H, s), 3.17-3.27 (1H, m), 3.52 (2H, q), 4.23-4.37 (1H, m), 7.24 (1H, d), 6.89 (1H, dd), 7.80 (1H, d), 10.20 (1H, br s) Example 39.1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6- (methylsulfonyl) -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E39 )

(E39)
6-Bromo-1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazole-2-DM in DMSO (1 ml) at room temperature under argon A stirred solution of ON (E14 free base) (130 mg, 0.31 mmol) was added to sodium methanesulfinate (35 mg, 0.34 mmol), copper (I) iodide (5.9 mg, 0.031 mmol) and sodium L-proline. After treatment with salt (8.5 mg, 0.062 mmol), it was heated at 95 ° C. for 18 hours. Additional sodium sulfinate (70 mg), copper (I) iodide (12 mg) and L-proline sodium salt (17 mg) were added and the mixture was heated at 95 ° C. for an additional 58 hours. The mixture was cooled and then treated with 10% Na ₂ CO ₃ solution (20 ml) and EtOAc (25 ml), shaken well and filtered through Kieselguhr. The EtOAc layer was isolated, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified using a Waters Xbridge chromatography column column eluting with acetonitrile / water / 0.1% formic acid to give the free base of the title compound as a white solid (12 mg). This was converted to the title compound as a yellow solid. MH + = 422
¹ H NMR (free base) δ (CDCl ₃ , 400MHz): 1.20-1.40 (4H, m), 1.21 (3H, t), 1.80-2.05 (4H, m), 2.10-2.20 (2H, m), 2.34 -2.52 (assuming 5H, m), 3.02-3.12 (assuming 2H, m), 3.10 (3H, s), 3.17-3.27 (1H, m), 3.52 (2H, q), 4.23-4.37 (1H, m), 7.24 (1H, d), 6.89 (1H, dd), 7.80 (1H, d), 10.20 (1H, br s)

（Ｅ４０）
０℃にてアルゴン下、ジクロロメタン（１０ｍｌ）中、４−メチル−Ｎ^２−｛１−［シス−４−（２−プロピン−１−イルオキシ）シクロヘキシル］−４−ピペリジニル｝−１，２−ベンゼンジアミン（Ｄ１３６、２００ｍｇ、０．５８ｍｍｏｌ）およびジイソプロピルエチルアミン（２００μｌ）の攪拌溶液を固体トリホスゲン（０．０７ｍｇ）で処理し、２時間攪拌した。この混合物をジクロロメタンで希釈し、希ＮａＨＣＯ_３溶液で洗浄し、硫酸ナトリウムで乾燥させ、溶媒を除去した。標題化合物をエーテルから白色固体として得た（１５６ｍｇ）。ＭＨ^＋＝３６８
¹H NMR δ(CDCl₃, 400 MHz): 1.45 (2H, m), 1.55-1.8 (obs, m), 1.85 (2H, m), 2.02 (2H , m), 2.4 (obs, m), 3.05 (2H, m), 3.75 (1H, m), 4.15 (2H, s), 4.34 (1H, m), 6.83 (1H, d), 6.92 (1H, d), 7.14 (1H, s), 8.44 (1H, s) Example 4 0.6-Methyl-1- {1- [cis-4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one ( E40)

(E40)
Under argon at 0 ° C., in dichloromethane (10 ml), 4-methyl ^-N 2 - {1- [cis-4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinyl} -1,2-benzene A stirred solution of diamine (D136, 200 mg, 0.58 mmol) and diisopropylethylamine (200 μl) was treated with solid triphosgene (0.07 mg) and stirred for 2 hours. The mixture was diluted with dichloromethane, washed with dilute NaHCO ₃ solution, dried over sodium sulfate and the solvent removed. The title compound was obtained from ether as a white solid (156 mg). MH ⁺ = 368
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.45 (2H, m), 1.55-1.8 (obs, m), 1.85 (2H, m), 2.02 (2H, m), 2.4 (obs, m), 3.05 (2H, m), 3.75 (1H, m), 4.15 (2H, s), 4.34 (1H, m), 6.83 (1H, d), 6.92 (1H, d), 7.14 (1H, s), 8.44 ( 1H, s)

（Ｅ４１）
０℃にてアルゴン下、ジクロロメタン（２０ｍｌ）中、４−メチル−Ｎ^２−｛１−［トランス−４−（２−プロピン−１−イルオキシ）シクロヘキシル］−４−ピペリジニル｝−１，２−ベンゼンジアミン（Ｄ１３７、２８０ｍｇ）およびジイソプロピルエチルアミン（０．３ｍｌ）の攪拌溶液を固体トリホスゲン（９７ｍｇ）で処理し、１時間攪拌した。この混合物をジクロロメタンで希釈し、希ＮａＨＣＯ_３溶液で洗浄し、ヒドロマトリックスで乾燥させ、溶媒を除去した。残渣をジクロロメタン−メタノール性アンモニア０〜１０％で溶出するシリカゲルでのクロマトグラフィーに付した。標題化合物を白色固体として得た（１８０ｍｇ）。ＭＨ^＋＝３６８
¹H NMR δ(CDCl₃, 400 MHz): 1.2-1.4 (5H, m), 1.8 (2H, m), 1.95 (1H, m), 2.12 (2H , m), 2.4 (8H, m), 3.06 (2H, m), 3.45 (1H, m), 4.19 (2H, s), 4.33 (H, m), 6.83 (1H, d), 6.93 (1H, d), 7.12 (1H, s), 8.17 (1H, s) Example 41.6-Methyl-1- {1- [trans-4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one ( E41)

(E41)
Under argon at 0 ° C., in dichloromethane (20 ml), 4-methyl ^-N 2 - {1- [trans-4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinyl} -1,2-benzene A stirred solution of diamine (D137, 280 mg) and diisopropylethylamine (0.3 ml) was treated with solid triphosgene (97 mg) and stirred for 1 hour. The mixture was diluted with dichloromethane, washed with dilute NaHCO ₃ solution, dried with hydromatrix and the solvent removed. The residue was chromatographed on silica gel eluting with dichloromethane-methanolic ammonia 0-10%. The title compound was obtained as a white solid (180 mg). MH ⁺ = 368
¹ H NMR δ (CDCl ₃ , 400 MHz): 1.2-1.4 (5H, m), 1.8 (2H, m), 1.95 (1H, m), 2.12 (2H, m), 2.4 (8H, m), 3.06 (2H, m), 3.45 (1H, m), 4.19 (2H, s), 4.33 (H, m), 6.83 (1H, d), 6.93 (1H, d), 7.12 (1H, s), 8.17 ( 1H, s)

（Ｅ４２）
０℃にてアルゴン下、ジクロロメタン（７ｍｌ）中、（２−アミノ−５−フルオロフェニル）｛１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジニル｝アミン（Ｄ１４７、９７ｍｇ、０．２７７ｍｍｏｌ）の攪拌溶液をジイソプロピルエチルアミン（７０μＬ、０．４１５ｍｍｏｌ、５３ｍｇ）、次いで固体トリホスゲン（３３ｍｇ、０．１１ｍｍｏｌ）で処理し、０℃で１時間攪拌した。この混合物を希ＮａＨＣＯ_３溶液（２０ｍｌ）で処理し、ジクロロメタンで抽出した（２×２５ｍｌ）。合わせた抽出液を乾燥させ（ＭｇＳＯ_４）、真空濃縮し、標題化合物の遊離塩基を得た。次に、この残渣をＥｔ_２Ｏ（５ｍｌ）で処理し、得られた沈殿を遊離塩基として回収した（３１ｍｇ）。次に、これを１Ｍ ＨＣｌ／ジエチルエーテル（０．２５ｍｌ）で処理し、２０分間攪拌し、固体を濾過し、標題化合物（３８ｍｇ、３３％）を白色固体として得た。ＭＨ^＋３７６
¹H NMR (遊離塩基) δ(CDCl₃, 400 MHz): 0.94 (3H, s), 1.19-1.26 (4H, m), 1.48-1.52 (2H, m), 1.64-1.70 (2H, m), 1.82-1.92 (4H, m), 2.22-2.36 (4H, m), 3.14-3.16 (2H, d), 3.43-3.53 (4H, m), 4.23-4.28 (1H, m), 6.74- 6.79 (1H), 6.95-7.02 (2H, m), 8.63 (1H, s) Example 42.1- {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -6-fluoro-1,3-dihydro-2H-benzimidazol-2-one hydrochloride ( E42)

(E42)
(2-Amino-5-fluorophenyl) {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} amine (D147, 97 mg) in dichloromethane (7 ml) under argon at 0 ° C. , 0.277 mmol) was treated with diisopropylethylamine (70 μL, 0.415 mmol, 53 mg) followed by solid triphosgene (33 mg, 0.11 mmol) and stirred at 0 ° C. for 1 hour. The mixture was treated with dilute NaHCO ₃ solution (20 ml) and extracted with dichloromethane (2 × 25 ml). The combined extracts were dried (MgSO ₄ ) and concentrated in vacuo to give the free base of the title compound. The residue was then treated with Et ₂ O (5 ml) and the resulting precipitate was collected as the free base (31 mg). This was then treated with 1M HCl / diethyl ether (0.25 ml), stirred for 20 minutes and the solid filtered to give the title compound (38 mg, 33%) as a white solid. MH ⁺ 376
¹ H NMR (free base) δ (CDCl ₃ , 400 MHz): 0.94 (3H, s), 1.19-1.26 (4H, m), 1.48-1.52 (2H, m), 1.64-1.70 (2H, m), 1.82-1.92 (4H, m), 2.22-2.36 (4H, m), 3.14-3.16 (2H, d), 3.43-3.53 (4H, m), 4.23-4.28 (1H, m), 6.74-6.79 (1H ), 6.95-7.02 (2H, m), 8.63 (1H, s)

（Ｅ４３）
室温にてアルゴン下、ＣＨ_２Ｃｌ_２（１０ｍＬ）中、（２−アミノ−５−フルオロフェニル）｛１−［トランス−４−（メチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジニル｝アミン（Ｄ１５５、２０５ｍｇ、０．６１ｍｍｏｌ）の溶液に、ジイソプロピルエチルアミン（２１０μＬ、１．２３ｍｍｏｌ）を加えた。この反応物を０℃まで冷却し、トリホスゲン（６９ｍｇ、０．２３ｍｍｏｌ）を少量ずつ加えた。この反応物を１時間攪拌した後、２Ｍ ＮａＯＨ（１０ｍＬ）を加えた。次に、この混合物をＣＨ_２Ｃｌ_２（２０ｍＬ）および飽和ＮａＨＣＯ_３（２０ｍＬ）で希釈した。水層をＣＨ_２Ｃｌ_２で抽出し（２回）、合わせた有機液を乾燥させ、回転蒸発により濃縮し、紫色の固体を得た。この残渣をＥｔＯＡｃ−Ｅｔ_２Ｏ（１：１、４ｍＬ）で処理して白色固体を得、これをトルエンと共沸させ（２×５ｍＬ）、標題化合物の遊離塩基を白色固体として得た。この遊離塩基をＭｅＯＨ（２ｍＬ）、次いでＥｔ_２Ｏ中１ＭのＨＣｌ（０．５８ｍＬ）で処理した。この混合物を３０分間攪拌した後、回転蒸発により溶媒を除去し、標題化合物（１０３ｍｇ、４２％）を淡黄色固体として得た。ＭＨ^＋３６２
¹H NMR δ(DMSO-d₆, 400 MHz): 1.22-1.38 (5 H, m), 1.78-2.08 (8 H, m), 2.73-2.88 (2H, m), 3.07-3.30 (3 H, m), 3.23 (3 H, s), 3.62-3.71 (2 H, m), 4.62 (1 H, m), 6.79-6.88 (1 H, m), 6.94-7.00 (1 H, m), 7.56 (1 H, m), 9.80 (1 H, m), 10.99 (1 H, s) Example 43.6-Fluoro-1- {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E43)

(E43)
(2-Amino-5-fluorophenyl) {1- [trans-4- (methyloxy) -1-methylcyclohexyl] -4-piperidinyl} amine (CH ₂ Cl ₂ (10 mL) at room temperature under argon) To a solution of D155, 205 mg, 0.61 mmol) was added diisopropylethylamine (210 μL, 1.23 mmol). The reaction was cooled to 0 ° C. and triphosgene (69 mg, 0.23 mmol) was added in small portions. The reaction was stirred for 1 hour before 2M NaOH (10 mL) was added. The mixture was then diluted with CH ₂ Cl ₂ (20 mL) and saturated NaHCO ₃ (20 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (twice) and the combined organics were dried and concentrated by rotary evaporation to give a purple solid. The residue was treated with EtOAc-Et ₂ O (1: 1, 4 mL) to give a white solid that was azeotroped with toluene (2 × 5 mL) to give the free base of the title compound as a white solid. The free base was treated with MeOH (2 mL) followed by 1M HCl in Et ₂ O (0.58 mL). The mixture was stirred for 30 minutes and then the solvent was removed by rotary evaporation to give the title compound (103 mg, 42%) as a pale yellow solid. MH ⁺ 362
¹ H NMR δ (DMSO-d ₆ , 400 MHz): 1.22-1.38 (5 H, m), 1.78-2.08 (8 H, m), 2.73-2.88 (2H, m), 3.07-3.30 (3 H, m), 3.23 (3 H, s), 3.62-3.71 (2 H, m), 4.62 (1 H, m), 6.79-6.88 (1 H, m), 6.94-7.00 (1 H, m), 7.56 (1 H, m), 9.80 (1 H, m), 10.99 (1 H, s)

（Ｅ４４）
室温にてアルゴン下、ＣＨ_２Ｃｌ_２（１０ｍＬ）中、（２−アミノ−５−クロロフェニル）｛１−［トランス−１−メチル−４−（メチルオキシ）シクロヘキシル］−４−ピペリジニル｝アミン（Ｄ１５７、３０５ｍｇ、０．８７ｍｍｏｌ）の溶液に、ジイソプロピルエチルアミン（２９０μＬ、１．７０ｍｍｏｌ）を加えた。この反応物を０℃まで冷却し、トリホスゲン（８６ｍｇ、０．２９ｍｍｏｌ）を少量ずつ加えた。この反応物を１時間攪拌した後、２Ｍ ＮａＯＨ（１０ｍＬ）を加えた。次に、この混合物をＣＨ_２Ｃｌ_２（２０ｍＬ）および飽和ＮａＨＣＯ_３（２０ｍＬ）で希釈した。水層をＣＨ_２Ｃｌ_２で抽出し（２回）、合わせた有機液を乾燥させ、回転蒸発により濃縮した。粗残渣をＣＨ_２Ｃｌ_２で処理し、濾過した。この固体をＥｔＯＡｃでトリチュレートして桃色固体を得、これをトルエンと共沸させ（６×２ｍＬ）、その後、温ＭｅＯＨ−ＣＨ_２Ｃｌ_２に溶解し、回転蒸発により溶媒を除去した。この固体をもう一度、温ＭｅＯＨ−ＣＨ_２Ｃｌ_２に溶解し、回転蒸発により溶媒を除去し、標題化合物の遊離塩基を灰白色固体として得た。遊離塩基をＭｅＯＨ（２ｍＬ）、次いでＥｔ_２Ｏ中１ＭのＨＣｌ（０．４５ｍＬ）に懸濁させた。この混合物を３０分間攪拌した後、回転蒸発により溶媒を除去し、標題化合物（９２ｍｇ、２６％）を淡桃色固体として得た。M(Cl-35)⁺ 378, M(Cl-37)H⁺ 380
¹H NMR δ(DMSO-d₆, 400 MHz): 1.24-1.38 (5 H, m), 1.71-1.82 (2 H, m), 1.90-2.08 (6H, m), 2.67-2.79 (2 H, m), 3.08-3.26 (3 H, m), 3.26 (3 H, s) 3.62-3.31 (2 H, m), 4.49 (1 H, m), 6.98-7.07 (2 H, m), 7.52-7.58 (1 H, m), 9.36 (1 H, m), 11.12 (1 H, s) Example 44.6-Chloro-1- {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E44)

(E44)
(2-Amino-5-chlorophenyl) {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} amine (D157) in CH ₂ Cl ₂ (10 mL) at room temperature under argon. , 305 mg, 0.87 mmol) was added diisopropylethylamine (290 μL, 1.70 mmol). The reaction was cooled to 0 ° C. and triphosgene (86 mg, 0.29 mmol) was added in small portions. The reaction was stirred for 1 hour before 2M NaOH (10 mL) was added. The mixture was then diluted with CH ₂ Cl ₂ (20 mL) and saturated NaHCO ₃ (20 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (twice) and the combined organics were dried and concentrated by rotary evaporation. The crude residue was treated with CH ₂ Cl ₂ and filtered. The solid was triturated with EtOAc to give a pink solid that was azeotroped with toluene (6 × 2 mL), then dissolved in warm MeOH—CH ₂ Cl ₂ and the solvent removed by rotary evaporation. This solid was once again dissolved in warm MeOH—CH ₂ Cl ₂ and the solvent was removed by rotary evaporation to give the free base of the title compound as an off-white solid. The free base was suspended in MeOH (2 mL) followed by 1M HCl in Et ₂ O (0.45 mL). The mixture was stirred for 30 minutes and then the solvent was removed by rotary evaporation to give the title compound (92 mg, 26%) as a pale pink solid. M (Cl-35) ⁺ 378, M (Cl-37) H ⁺ 380
¹ H NMR δ (DMSO-d ₆ , 400 MHz): 1.24-1.38 (5 H, m), 1.71-1.82 (2 H, m), 1.90-2.08 (6H, m), 2.67-2.79 (2 H, m), 3.08-3.26 (3 H, m), 3.26 (3 H, s) 3.62-3.31 (2 H, m), 4.49 (1 H, m), 6.98-7.07 (2 H, m), 7.52- 7.58 (1 H, m), 9.36 (1 H, m), 11.12 (1 H, s)

（Ｅ４５）
氷浴温度で攪拌した４−（エチルオキシ）−Ｎ^２−｛１−［トランス−１−メチル−４−（メチルオキシ）シクロヘキシル］−４−ピペリジニル｝−１，２−ベンゼンジアミン（Ｄ１６０、０．２６ｇ，）、ジクロロメタン（２０ｍｌ）およびジイソプロピルエチルアミン（１ｍｌ）の溶液に、トリホスヘン（０．０８２ｇ）を加えた。この溶液を室温で一晩攪拌した後、飽和重炭酸ナトリウム溶液で洗浄し、溶媒を除去した。残渣を０〜１０％ジクロロメタン−メタノール性アンモニアで溶出するシリカゲルでのクロマトグラフィーに付し、標題化合物の遊離塩基を白色固体として得た（０．１２ｇ）。これをジクロロメタンに溶解し、エーテル中の塩化水素で処理し、溶媒を除去し、標題化合物をジエチルエーテルから白色固体として得た（０．１０５ｇ）。ＭＨ^＋＝３８８
¹H NMR δ(d⁶DMSO, 400 MHz) (遊離塩基): 0.93 (3H, s), 1.45-1.7 (〜11H, m), 1.8-2.0 (4H, m), 2.2-2.4 (4H, m), 3.1 (2H, m), 3.3 (obs, m), 4.05 (2H, m), 6.59 (1H, d of d), 6.86 (1H, d), 6.92 (1H, d), 8.65 (1H, s) Example 45.6- (Ethyloxy) -1- {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one Hydrochloride (E45)

(E45)
4- (Ethyloxy) -N ^2- {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D160, 0.00) stirred at ice bath temperature. To a solution of 26 g,), dichloromethane (20 ml) and diisopropylethylamine (1 ml) was added triphosphene (0.082 g). The solution was stirred overnight at room temperature and then washed with saturated sodium bicarbonate solution to remove the solvent. The residue was chromatographed on silica gel eluting with 0-10% dichloromethane-methanolic ammonia to give the free base of the title compound as a white solid (0.12 g). This was dissolved in dichloromethane, treated with hydrogen chloride in ether, the solvent was removed, and the title compound was obtained as a white solid from diethyl ether (0.105 g). MH ⁺ = 388
¹ H NMR δ (d ⁶ DMSO, 400 MHz) (free base): 0.93 (3H, s), 1.45-1.7 (~ 11H, m), 1.8-2.0 (4H, m), 2.2-2.4 (4H, m ), 3.1 (2H, m), 3.3 (obs, m), 4.05 (2H, m), 6.59 (1H, d of d), 6.86 (1H, d), 6.92 (1H, d), 8.65 (1H, s)

（Ｅ４６）
氷浴温度で攪拌した４−（エチルオキシ）−Ｎ^２−｛１−［トランス−１−メチル−４−（エチルオキシ）シクロヘキシル］−４−ピペリジニル｝−１，２−ベンゼンジアミン（Ｄ１６２、０．０９ｇ）、ジクロロメタン（１０ｍｌ）およびジイソプロピルエチルアミン（１ｍｌ）の溶液に、トリホスヘン（０．０２ｇ）を加えた。この溶液を室温で一晩攪拌した後、飽和重炭酸ナトリウム溶液で洗浄し、溶媒を除去した。残渣を０〜１０％ジクロロメタン−メタノール性アンモニアで溶出するシリカゲルでのクロマトグラフィーに付し、標題化合物の遊離塩基を油状物として得た（０．０８ｇ）。これをジクロロメタンに溶解し、エーテル中の塩化水素で処理し、溶媒を除去し、標題化合物をジエチルエーテルから白色固体として得た（０．０６７ｇ）。ＭＨ^＋＝４０２
¹H NMR δ(d⁶DMSO, 250 MHz) (遊離塩基): 0.94 (3H, s), 1.22 (3H, t), 1.4-1.7 (obs, m), 1.8-2.0 (4H, m), 2.2-2.4 (4H, m), 3.15 (2H, m), 34-3.6 (3H, m), 4.05 (2H, q), 4.25 (1H, m), 6.60 (1H, d of d), 6.80 (1H, d), 7.00 (1H, d), 9.8 (1H, s) Example 46.6- (Ethyloxy) -1- {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloric acid Salt (E46)

(E46)
It was stirred at ice bath temperature 4- ^(ethyloxy) -N 2 - {1- [frans-1-methyl-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,2-benzenediamine (D162,0.09G ), Dichloromethane (10 ml) and diisopropylethylamine (1 ml) in a solution of triphosphene (0.02 g). The solution was stirred overnight at room temperature and then washed with saturated sodium bicarbonate solution to remove the solvent. The residue was chromatographed on silica gel eluting with 0-10% dichloromethane-methanolic ammonia to give the free base of the title compound as an oil (0.08 g). This was dissolved in dichloromethane, treated with hydrogen chloride in ether, the solvent was removed, and the title compound was obtained as a white solid from diethyl ether (0.067 g). MH ⁺ = 402
¹ H NMR δ (d ⁶ DMSO, 250 MHz) (free base): 0.94 (3H, s), 1.22 (3H, t), 1.4-1.7 (obs, m), 1.8-2.0 (4H, m), 2.2 -2.4 (4H, m), 3.15 (2H, m), 34-3.6 (3H, m), 4.05 (2H, q), 4.25 (1H, m), 6.60 (1H, d of d), 6.80 (1H , d), 7.00 (1H, d), 9.8 (1H, s)

（Ｅ４７）
室温にてアルゴン下、ＣＨ_２Ｃｌ_２（１０ｍＬ）中、（２−アミノ−５−クロロフェニル）｛１−［トランス−４−（エチルオキシ）−１−メチルシクロヘキシル］−４−ピペリジニル｝アミン（Ｄ１６４、１３９ｍｇ、０．３８ｍｍｏｌ）の溶液に、固相支持ジイイソプロピルベンジルアミン（２９３ｍｇ、１．０４ｍｍｏｌ）を加えた。この反応物を０℃まで冷却し、トリホスゲン（４２ｍｇ、０．１４ｍｍｏｌ）を少量ずつ加えた。この反応物を２時間攪拌した後、２Ｍ ＮａＯＨ（１０ｍＬ）を加えた。次に、この混合物を濾過し、飽和ＮａＨＣＯ_３溶液で洗浄した。水層をＣＨ_２Ｃｌ_２で抽出し（２回）、合わせた有機液を乾燥させ（Ｎａ_２ＳＯ_４）、回転蒸発により濃縮し、褐色固体を得た。この固体をＥｔＯＡｃでトリチュレートして淡褐色固体を得、これをクロマトグラフィー（アミンドープシリカ、ヘキサン−ＥｔＯＡｃ）により精製し、標題化合物の遊離塩基を淡褐色固体として得た。この遊離塩基をＭｅＯＨ（２ｍＬ）に懸濁させた後、Ｅｔ_２Ｏ中１ＭのＨＣｌ（０．３３ｍＬ）を加えた。この混合物を３０分間攪拌した後、濾過し、標題化合物（６３ｍｇ、３８％）を淡桃色固体として得た。
M(Cl-35)⁺ 392, M(Cl-37)H⁺ 394
¹H NMR δ(DMSO-d₆, 400 MHz): 1.10 (3 H, t, J 7), 1.28-1.40 (5 H, m), 1.76 (2 H, m), 1.90-2.05 (6 H, m), 2.71 (2 H, m), 3.15 (3 H, m), 3.48 (2 H, q, J 7), 3.66 (2 H, m), 4.58 (1 H, m), 7.02 (2 H, m), 7.55 (1 H, s), 9.34 (1 H, m), 11.11 (1 H, s) Example 47.6-Chloro-1- {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one hydrochloride ( E47)

(E47)
(2-Amino-5-chlorophenyl) {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} amine (D164, in CH ₂ Cl ₂ (10 mL) at room temperature under argon. Solid solution supported diisopropylbenzylamine (293 mg, 1.04 mmol) was added to a solution of 139 mg, 0.38 mmol). The reaction was cooled to 0 ° C. and triphosgene (42 mg, 0.14 mmol) was added in small portions. The reaction was stirred for 2 hours before 2M NaOH (10 mL) was added. The mixture was then filtered and washed with saturated NaHCO ₃ solution. The aqueous layer was extracted with CH ₂ Cl ₂ (twice) and the combined organics were dried (Na ₂ SO ₄ ) and concentrated by rotary evaporation to give a brown solid. The solid was triturated with EtOAc to give a light brown solid which was purified by chromatography (amine doped silica, hexane-EtOAc) to give the free base of the title compound as a light brown solid. The free base was suspended in MeOH (2 mL) and 1M HCl in Et ₂ O (0.33 mL) was added. The mixture was stirred for 30 minutes and then filtered to give the title compound (63 mg, 38%) as a pale pink solid.
M (Cl-35) ⁺ 392, M (Cl-37) H ⁺ 394
¹ H NMR δ (DMSO-d ₆ , 400 MHz): 1.10 (3 H, t, J 7), 1.28-1.40 (5 H, m), 1.76 (2 H, m), 1.90-2.05 (6 H, m), 2.71 (2 H, m), 3.15 (3 H, m), 3.48 (2 H, q, J 7), 3.66 (2 H, m), 4.58 (1 H, m), 7.02 (2 H , m), 7.55 (1 H, s), 9.34 (1 H, m), 11.11 (1 H, s)

Claims (17)

Formula (I):

[Where:
R ⁶ is hydrogen, cyano, _{halogen, C 1-6} alkyl, 1 or more _{C 1-6} alkyl substituted with a fluorine _{atom, C 1-6 alkylsulfonyl, C 3-6} cycloalkyl, one or more fluorine atoms in substituted _{C 3-6 cycloalkyl,} it is selected from _{C 1-6} alkoxy, and one or more _{C 1-6} alkoxy substituted with a fluorine atom;
R is C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-6 alkyl and C _2-6 alkynyl (any alkyl group or cycloalkyl group optionally has one or more fluorine atoms) And Q is hydrogen or C _1-6 alkyl]
Or a salt or solvate thereof. R ⁶ is hydrogen, cyano, _{halogen, C 1-6} alkyl, 1, 2 or 3 _{C 1-6} alkyl substituted with a fluorine _{atom, C 3-6 cycloalkyl, C 1-6} alkylsulfonyl, C _1-6 alkoxy, and one, two or selected from 3 _{C 1-6} alkoxy substituted with a fluorine atom, a compound according to claim 1. A compound according to claim 2, wherein R ⁶ is selected from hydrogen, cyano, fluoro, bromo, methyl, ethyl, methoxy, trifluoromethoxy, methylsulfonyl, trifluoromethyl and cyclopropyl. R is selected from C _1-6 alkyl, C _3-6 cycloalkyl and C _3-6 cycloalkylC _1-6 alkyl, any alkyl or cycloalkyl group optionally having 1, 2 or 3 The compound according to any one of claims 1 to 3, which may be substituted with a fluorine atom. R is methyl, ethyl, propyl, isopropyl, CF _3, cyclopropylmethyl, is selected from propynyl and cyclobutyl 5. The compound of claim 4, wherein. 6. A compound according to any one of claims 1 to 5, wherein Q is selected from hydrogen and _C1-3 alkyl. 1. 6-Methyl-1- [1- (cis-4-methoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 6-Methyl-1- [1- (trans-4-methoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6-methyl-1,3-dihydro-2H-benzimidazol-2-one 1- {1- [cis-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6-methyl-1,3-dihydro-2H-benzimidazol-2-one 6-Methyl-1- {1- [cis-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6. 6-methyl-1- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6. 6-methyl-1- (1- {trans-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one 6. 6-methyl-1- {1- [cis-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6-Methyl-1- {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6-Methyl-1- (1- {cis-4-[(1-methylethyl) oxy] cyclohexyl} -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one Cis- (1- [4- (Ethoxyl) cyclohexyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one Trans 1- (1- [4- (Ethoxyl) cyclohexyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one13. 1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6-fluoro-1,3-dihydro-2H-benzimidazol-2-one; 6. 6-Bromo-1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 1- {1- [cis-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6- (trifluoromethyl) -1,3-dihydro-2H-benzimidazol-2-one 6. 6-ethyl-1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6. 6-cyclopropyl-1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6- (methyloxy) -1,3-dihydro-2H-benzimidazol-2-one Cis-1- {1- [4- (ethoxy) cyclohexyl] -4-piperidinyl} -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one20. Trans-1- {1- [4- (ethoxy) cyclohexyl] -4-piperidinyl} -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one 21. 6-Methyl-1- [1- (4-trifluoromethoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 1- (1- {cis-4-[(cyclopropylmethyl) oxy] cyclohexyl} -4-piperidinyl) -6-methyl-1,3-dihydro-2H-benzimidazol-2-one; 1- (1- {trans-4-[(cyclopropylmethyl) oxy] cyclohexyl} -4-piperidinyl) -6-methyl-1,3-dihydro-2H-benzimidazol-2-one; Trans-6-methyl-1- [1- (4-cyclopropyloxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one Cis-1- (1- [4- (propyloxy) cyclohexyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one Trans-1- (1- [4- (propyloxy) cyclohexyl] -4-piperidinyl) -1,3-dihydro-2H-benzimidazol-2-one 6-Bromo-1- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6-Ethyl-1- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6-cyclopropyl-1- {1- [trans-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one Cis-1- {1- [4- (propyloxy) cyclohexyl] -4-piperidinyl} -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one Trans-1- {1- [4- (propyloxy) cyclohexyl] -4-piperidinyl} -6-[(trifluoromethyl) oxy] -1,3-dihydro-2H-benzimidazol-2-one 1- {1- [cis-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -6-methyl-1,3-dihydro-2H-benzimidazol-2-one 1- {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -6-methyl-1,3-dihydro-2H-benzimidazol-2-one 6-Methyl-1- {1- [cis-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6-Methyl-1- {1- [trans-1-methyl-4- (propyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one Trans-6-methyl-1- [1- (1-ethyl-4-propoxycyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one 3- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile 38. 3- {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile 39. 1- {1- [trans-4- (ethyloxy) cyclohexyl] -4-piperidinyl} -6- (methylsulfonyl) -1,3-dihydro-2H-benzimidazol-2-one 6-Methyl-1- {1- [cis-4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6-Methyl-1- {1- [trans-4- (2-propyn-1-yloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 1- {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -6-fluoro-1,3-dihydro-2H-benzimidazol-2-one 6-Fluoro-1- {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one; 6-Chloro-1- {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6- (Ethyloxy) -1- {1- [trans-1-methyl-4- (methyloxy) cyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6- (Ethyloxy) -1- {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one 6-chloro-1- {1- [trans-4- (ethyloxy) -1-methylcyclohexyl] -4-piperidinyl} -1,3-dihydro-2H-benzimidazol-2-one and its salts and solvates The compound of claim 1, wherein   A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.   The compound according to any one of claims 1 to 7, which is used for treatment. Used to treat conditions which require promoting action muscarinic M ₁ receptor, the compounds according to any one of claims 1 to 7.   8. A compound according to any one of claims 1 to 7 for use in the treatment of a psychotic disorder or cognitive disorder. In the manufacture of a medicament for the treatment of conditions which require promoting action muscarinic M ₁ receptor, Use of a compound according to any one of claims 1-7.   Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of a psychotic disorder or cognitive disorder. A method of treating conditions which require promoting action muscarinic M ₁ receptor, administering a compound according to any one of claims 1 to 7 effective amount to a mammal in need thereof Including a method.   A method of treating a psychotic disorder or cognitive disorder comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1-7. A method for producing the compound of claim 1, comprising:
(I) Formula (II):

Wherein R ^{6 ′} is a group R ⁶ defined in claim 1 or a group convertible to R ⁶ .
And a compound of formula (III):

Wherein R ′ is a group R as defined in claim 1 or a group convertible to R under conditions suitable for reductive alkylation.
A method comprising coupling a compound of (A1);
(Ii) a compound of formula (II) as defined for process (A1) and a compound of formula (III) as defined for process (A1) in the presence of a source of cyanide under conditions suitable for a Grignard reaction. Reaction to cyano intermediate (XXXX):

Wherein R ^{6 ′} is a group R ⁶ or a group convertible to R ⁶ as defined in claim 1, and R ′ is a group R or a group convertible to R as defined in claim 1. Q is C ₁₆ alkyl and X is bromo, iodo or chloro.
A method (A2) comprising:
(Iii) Formula (IV):

Wherein R ^{6 ′} is a group R ⁶ or a group convertible to R ⁶ as defined in claim 1, and R ′ is a group R or a group convertible to R as defined in claim 1. And Q is as defined in claim 1)
And a compound of formula (V):

(Wherein X and Y both represent a leaving group)
A process (B) comprising reacting a compound of claim 1 optionally in an inert solvent, optionally in the presence of a base, optionally with heating;
(Iv) Formula (VI):

Wherein R ^{6 ′} is a group R ⁶ or a group convertible to R ⁶ as defined in claim 1, and R ′ is a group R or a group convertible to R as defined in claim 1. Q is as defined in claim 1 and Z is a leaving group such as bromo, iodo, chloro or triflate)
A method (C) comprising treating a compound of 1 with a palladium or copper catalyst (VII) to effect intramolecular cyclization;
(V) Formula (VIII):

Wherein R ^{6 ′} is a group R ⁶ defined in claim 1 or a group convertible to R ⁶ .
And a compound of formula (IX):

Wherein R ′ is a group R defined in claim 1 or a group convertible to R, Q is as defined in claim 1 and R ^a is C _1-5 alkyl. )
(D), which comprises coupling the compound by heating in an inert solvent such as xylene followed by reduction of the piperidine double bond;
(Vi) Formula (X):

Wherein R ^{6 ′} is a group R ⁶ or a group convertible to R ⁶ as defined in claim 1, and R ′ is a group R or a group convertible to R as defined in claim 1. And Q is as defined in claim 1)
And (vii) formula (XI) comprising reacting a compound of: and a reagent / reagent combination to effect a Curtius rearrangement of compound (X) followed by intramolecular cyclization;

Wherein R ^{6 ′} is a group R ⁶ defined in claim 1 or a group convertible to R ⁶ .
And a compound of formula (XII):

Wherein R ′ is a group R defined in claim 1 or a group convertible to R, Q is as defined in claim 1 and Z is hydroxy or a leaving group.
Performing a method selected from method (F) comprising coupling a compound of the above under alkylation or Mitsunobu reaction conditions, and then for any of the above methods,
Removing the protecting group and / or converting a compound of formula (I) or a salt or solvate thereof to another compound of formula (I) or a salt or solvate thereof. A compound of formula (II) or a salt or solvate thereof, or a compound of formula (IV) or a salt or solvate thereof, or a compound of formula (VI) or a salt or solvate thereof, or of formula (X) Compound or salt or solvate thereof:

[Wherein, in each of formula (II), formula (IV), formula (VI) and formula (X), R ^{6 ′} is a group R ⁶ defined in claim 1 or a group convertible to R ⁶⁾ And Z is a leaving group].